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Showing papers in "Protein Science in 2018"


Journal ArticleDOI
TL;DR: This article highlights some specific advances in the areas of visualization and usability, performance, and extensibility in ChimeraX.
Abstract: UCSF ChimeraX is next-generation software for the visualization and analysis of molecular structures, density maps, 3D microscopy, and associated data. It addresses challenges in the size, scope, and disparate types of data attendant with cutting-edge experimental methods, while providing advanced options for high-quality rendering (interactive ambient occlusion, reliable molecular surface calculations, etc.) and professional approaches to software design and distribution. This article highlights some specific advances in the areas of visualization and usability, performance, and extensibility. ChimeraX is free for noncommercial use and is available from http://www.rbvi.ucsf.edu/chimerax/ for Windows, Mac, and Linux.

2,866 citations


Journal ArticleDOI
TL;DR: Due to wide application of MolProbity validation and corrections by the research community, in Phenix, and at the worldwide Protein Data Bank, newly deposited structures have continued to improve greatly as measured by Mol probity's unique all‐atom clashscore.
Abstract: This paper describes the current update on macromolecular model validation services that are provided at the MolProbity website, emphasizing changes and additions since the previous review in 2010. There have been many infrastructure improvements, including rewrite of previous Java utilities to now use existing or newly written Python utilities in the open-source CCTBX portion of the Phenix software system. This improves long-term maintainability and enhances the thorough integration of MolProbity-style validation within Phenix. There is now a complete MolProbity mirror site at http://molprobity.manchester.ac.uk. GitHub serves our open-source code, reference datasets, and the resulting multi-dimensional distributions that define most validation criteria. Coordinate output after Asn/Gln/His "flip" correction is now more idealized, since the post-refinement step has apparently often been skipped in the past. Two distinct sets of heavy-atom-to-hydrogen distances and accompanying van der Waals radii have been researched and improved in accuracy, one for the electron-cloud-center positions suitable for X-ray crystallography and one for nuclear positions. New validations include messages at input about problem-causing format irregularities, updates of Ramachandran and rotamer criteria from the million quality-filtered residues in a new reference dataset, the CaBLAM Cα-CO virtual-angle analysis of backbone and secondary structure for cryoEM or low-resolution X-ray, and flagging of the very rare cis-nonProline and twisted peptides which have recently been greatly overused. Due to wide application of MolProbity validation and corrections by the research community, in Phenix, and at the worldwide Protein Data Bank, newly deposited structures have continued to improve greatly as measured by MolProbity's unique all-atom clashscore.

2,355 citations


Journal ArticleDOI
TL;DR: Some recent additions to Clustal Omega are described and some alternative ways of making alignments are benchmarked based on protein structure comparisons or predictions and include a recently described method based on secondary structure prediction.
Abstract: Clustal Omega is a widely used package for carrying out multiple sequence alignment. Here, we describe some recent additions to the package and benchmark some alternative ways of making alignments. These benchmarks are based on protein structure comparisons or predictions and include a recently described method based on secondary structure prediction. In general, Clustal Omega is fast enough to make very large alignments and the accuracy of protein alignments is high when compared to alternative packages. The package is freely available as executables or source code from www.clustal.org or can be run on-line from a variety of sites, especially the EBI www.ebi.ac.uk.

1,045 citations


Journal ArticleDOI
TL;DR: PDBsum is a web server providing structural information on the entries in the Protein Data Bank, primarily image‐based and include protein secondary structure, protein‐ligand and protein‐DNA interactions, PROCHECK analyses of structural quality, and many others.
Abstract: PDBsum is a web server providing structural information on the entries in the Protein Data Bank (PDB). The analyses are primarily image-based and include protein secondary structure, protein-ligand and protein-DNA interactions, PROCHECK analyses of structural quality, and many others. The 3D structures can be viewed interactively in RasMol, PyMOL, and a JavaScript viewer called 3Dmol.js. Users can upload their own PDB files and obtain a set of password-protected PDBsum analyses for each. The server is freely accessible to all at: http://www.ebi.ac.uk/pdbsum.

740 citations


Journal ArticleDOI
TL;DR: The present article comprehensively describes the HPA database functions and how users can utilize it for their own research as well as discusses the future path of spatial proteomics.
Abstract: The correct spatial distribution of proteins is vital for their function and often mis-localization or ectopic expression leads to diseases For more than a decade, the Human Protein Atlas (HPA) has constituted a valuable tool for researchers studying protein localization and expression in human tissues and cells The centerpiece of the HPA is its unique antibody collection for mapping the entire human proteome by immunohistochemistry and immunocytochemistry By these approaches, more than 10 million images showing protein expression patterns at a single-cell level were generated and are publicly available at wwwproteinatlasorg The antibody-based approach is combined with transcriptomics data for an overview of global expression profiles The present article comprehensively describes the HPA database functions and how users can utilize it for their own research as well as discusses the future path of spatial proteomics

572 citations


Journal ArticleDOI
TL;DR: The Adaptive Poisson-Boltzmann Solver (APBS) as mentioned in this paper was developed to solve the equations of continuum electrostatics for large biomolecular assemblages that have provided impact in the study of a broad range of chemical, biological and biomedical applications.
Abstract: The Adaptive Poisson-Boltzmann Solver (APBS) software was developed to solve the equations of continuum electrostatics for large biomolecular assemblages that have provided impact in the study of a broad range of chemical, biological, and biomedical applications. APBS addresses the three key technology challenges for understanding solvation and electrostatics in biomedical applications: accurate and efficient models for biomolecular solvation and electrostatics, robust and scalable software for applying those theories to biomolecular systems, and mechanisms for sharing and analyzing biomolecular electrostatics data in the scientific community. To address new research applications and advancing computational capabilities, we have continually updated APBS and its suite of accompanying software since its release in 2001. In this article, we discuss the models and capabilities that have recently been implemented within the APBS software package including a Poisson-Boltzmann analytical and a semi-analytical solver, an optimized boundary element solver, a geometry-based geometric flow solvation model, a graph theory-based algorithm for determining pKa values, and an improved web-based visualization tool for viewing electrostatics.

541 citations


Journal ArticleDOI
TL;DR: The molecular details of the cytokine‐induced signaling cascade are reviewed and the architectures of the proteins involved are described, including the receptors, kinases, and transcription factors that initiate and propagate signaling and the regulatory proteins that control it.
Abstract: More than 50 cytokines signal via the JAK/STAT pathway to orchestrate hematopoiesis, induce inflammation and control the immune response. Cytokines are secreted glycoproteins that act as intercellular messengers, inducing proliferation, differentiation, growth, or apoptosis of their target cells. They act by binding to specific receptors on the surface of target cells and switching on a phosphotyrosine-based intracellular signaling cascade initiated by kinases then propagated and effected by SH2 domain-containing transcription factors. As cytokine signaling is proliferative and often inflammatory, it is tightly regulated in terms of both amplitude and duration. Here we review molecular details of the cytokine-induced signaling cascade and describe the architectures of the proteins involved, including the receptors, kinases, and transcription factors that initiate and propagate signaling and the regulatory proteins that control it.

388 citations


Journal ArticleDOI
TL;DR: Recent progress on understanding the complex mechanism of action of NRs is discussed, primarily from a structural perspective and future studies are suggested to improve the understanding of NR signaling and better design drugs by integrating multiple structural and biophysical approaches.
Abstract: Nuclear receptors (NRs) are a family of transcription factors that regulate numerous physiological processes such as metabolism, reproduction, inflammation, as well as the circadian rhythm. NRs sense changes in lipid metabolite levels to drive differential gene expression, producing distinct physiologic effects. This is an allosteric process whereby binding a cognate ligand and specific DNA sequences drives the recruitment of diverse transcriptional co-regulators at chromatin and ultimately transactivation or transrepression of target genes. Dysregulation of NR signaling leads to various malignances, metabolic disorders, and inflammatory disease. Given their important role in physiology and ability to respond to small lipophilic ligands, NRs have emerged as valuable therapeutic targets. Here, we summarize and discuss the recent progress on understanding the complex mechanism of action of NRs, primarily from a structural perspective. Finally, we suggest future studies to improve our understanding of NR signaling and better design drugs by integrating multiple structural and biophysical approaches.

249 citations


Journal ArticleDOI
TL;DR: RCSB PDB resources are described in detail together with metrics documenting the impact of access to PDB data on basic and applied research, clinical medicine, education, and the economy.
Abstract: The Protein Data Bank (PDB) is one of two archival resources for experimental data central to biomedical research and education worldwide (the other key Primary Data Archive in biology being the International Nucleotide Sequence Database Collaboration). The PDB currently houses >134,000 atomic level biomolecular structures determined by crystallography, NMR spectroscopy, and 3D electron microscopy. It was established in 1971 as the first open-access, digital-data resource in biology, and is managed by the Worldwide Protein Data Bank partnership (wwPDB; wwpdb.org). US PDB operations are conducted by the RCSB Protein Data Bank (RCSB PDB; RCSB.org; Rutgers University and UC San Diego) and funded by NSF, NIH, and DoE. The RCSB PDB serves as the global Archive Keeper for the wwPDB. During calendar 2016, >591 million structure data files were downloaded from the PDB by Data Consumers working in every sovereign nation recognized by the United Nations. During this same period, the RCSB PDB processed >5300 new atomic level biomolecular structures plus experimental data and metadata coming into the archive from Data Depositors working in the Americas and Oceania. In addition, RCSB PDB served >1 million RCSB.org users worldwide with PDB data integrated with ∼40 external data resources providing rich structural views of fundamental biology, biomedicine, and energy sciences, and >600,000 PDB101.rcsb.org educational website users around the globe. RCSB PDB resources are described in detail together with metrics documenting the impact of access to PDB data on basic and applied research, clinical medicine, education, and the economy.

207 citations


Journal ArticleDOI
TL;DR: Xplor‐NIH is a popular software package for biomolecular structure determination from nuclear magnetic resonance (NMR) and other data sources, and some of its most useful data‐associated energy terms are reviewed.
Abstract: Xplor-NIH is a popular software package for biomolecular structure determination from nuclear magnetic resonance (NMR) and other data sources. Here, some of Xplor-NIH's most useful data-associated energy terms are reviewed, including newer alternative options for using residual dipolar coupling data in structure calculations. Further, we discuss new developments in the implementation of strict symmetry for the calculation of symmetric homo-oligomers, and in the representation of the system as an ensemble of structures to account for motional effects. Finally, the different available force fields are presented, among other Xplor-NIH capabilities.

150 citations


Journal ArticleDOI
TL;DR: It is still unclear how the actions of these various proteins and multiple other components that control release are integrated and, in particular, how they induce membrane fusion, but it can be expected that these fundamental questions can be answered in the near future.
Abstract: Research for three decades and major recent advances have provided crucial insights into how neurotransmitters are released by Ca2+ -triggered synaptic vesicle exocytosis, leading to reconstitution of basic steps that underlie Ca2+ -dependent membrane fusion and yielding a model that assigns defined functions for central components of the release machinery. The soluble N-ethyl maleimide sensitive factor attachment protein receptors (SNAREs) syntaxin-1, SNAP-25, and synaptobrevin-2 form a tight SNARE complex that brings the vesicle and plasma membranes together and is key for membrane fusion. N-ethyl maleimide sensitive factor (NSF) and soluble NSF attachment proteins (SNAPs) disassemble the SNARE complex to recycle the SNAREs for another round of fusion. Munc18-1 and Munc13-1 orchestrate SNARE complex formation in an NSF-SNAP-resistant manner by a mechanism whereby Munc18-1 binds to synaptobrevin and to a self-inhibited "closed" conformation of syntaxin-1, thus forming a template to assemble the SNARE complex, and Munc13-1 facilitates assembly by bridging the vesicle and plasma membranes and catalyzing opening of syntaxin-1. Synaptotagmin-1 functions as the major Ca2+ sensor that triggers release by binding to membrane phospholipids and to the SNAREs, in a tight interplay with complexins that accelerates membrane fusion. Many of these proteins act as both inhibitors and activators of exocytosis, which is critical for the exquisite regulation of neurotransmitter release. It is still unclear how the actions of these various proteins and multiple other components that control release are integrated and, in particular, how they induce membrane fusion, but it can be expected that these fundamental questions can be answered in the near future, building on the extensive knowledge already available.

Journal ArticleDOI
TL;DR: In this article, the authors analyzed infrared consistency conditions of 3D and 4D effective field theories with massive scalars or fermions charged under multiple U(1) gauge fields and showed that the theories need to contain bifundamentals and satisfya version of the weak gravity conjecture known as the convex hull condition.
Abstract: We analyze infrared consistency conditions of 3D and 4D effective field theories withmassive scalars or fermions charged under multiple U(1) gauge fields. At low energies, one can integrate out the massive particles andthus obtain a one‐loop effective action for the gauge fields. In the regime wherecharge‐independent contributions to higher‐derivative terms in the action are sufficientlysmall, it is then possible to derive constraints on the charge‐to‐mass ratios of themassive particles from requiring that photons propagate causally and have an analyticS‐matrix. We thus find that the theories need to contain bifundamentals and satisfya version of the weak gravity conjecture known as the convex‐hull condition. Demandingself‐consistency of the constraints under Kaluza‐Klein compactification, we furthermoreshow that, for scalars, they imply a stronger version of the weak gravity conjecturein which the charge‐to‐mass ratios of an infinite tower of particles are bounded frombelow. We find that the tower must again include bifundamentals but does not necessarilyhave to occupy a charge (sub‐)lattice.

Journal ArticleDOI
TL;DR: The energy estimation method underlying IUPred is reviewed and how the prediction output can be interpreted in a more complex case by taking into account the heterogeneous nature of IDRs is illustrated.
Abstract: Many proteins contain intrinsically disordered regions (IDRs), functional polypeptide segments that in isolation adopt a highly flexible conformational ensemble instead of a single, well-defined structure. Disorder prediction methods, which can discriminate ordered and disordered regions from the amino acid sequence, have contributed significantly to our current understanding of the distinct properties of intrinsically disordered proteins by enabling the characterization of individual examples as well as large-scale analyses of these protein regions. One popular method, IUPred provides a robust prediction of protein disorder based on an energy estimation approach that captures the fundamental difference between the biophysical properties of ordered and disordered regions. This paper reviews the energy estimation method underlying IUPred and the basic properties of the web server. Through an example, it also illustrates how the prediction output can be interpreted in a more complex case by taking into account the heterogeneous nature of IDRs. Various applications that benefited from IUPred to provide improved disorder predictions, complementing domain annotations and aiding the identification of functional short linear motifs are also described here. IUPred is freely available for noncommercial users through the web server (http://iupred.enzim.hu and http://iupred.elte.hu) . The program can also be downloaded and installed locally for large-scale analyses.

Journal ArticleDOI
TL;DR: In this article, the authors consider subregion complexity within the AdS3/CFT2 correspondence and show that the complexity of a reduced density matrix is given by the spacetime volume contained inside the associated Ryu-Takayanagi (RT) surface, in terms of an integral over the curvature.
Abstract: We consider subregion complexity within the AdS3/CFT2 correspondence. We rewrite the volume proposal, according to which the complexityof a reduced density matrix is given by the spacetime volume contained inside theassociated Ryu‐Takayanagi (RT) surface, in terms of an integral over the curvature.Using the Gauss‐Bonnet theorem we evaluate this quantity for general entangling regionsand temperature. In particular, we find that the discontinuity that occurs under achange in the RT surface is given by a fixed topological contribution, independentof the temperature or details of the entangling region. We offer a definition andinterpretation of subregion complexity in the context of tensor networks, and shownumerically that it reproduces the qualitative features of the holographic computationin the case of a random tensor network using its relation to the Ising model. Finally,we give a prescription for computing subregion complexity directly in CFT using thekinematic space formalism, and use it to reproduce some of our explicit gravity resultsobtained at zero temperature. We thus obtain a concrete matching of results for subregioncomplexity between the gravity and tensor network approaches, as well as a CFT prescription.

Journal ArticleDOI
Gunnar Jeschke1
TL;DR: MMM (Multiscale Modeling of Macromolecules) is a Matlab‐based open‐source modeling toolbox for this purpose with a particular emphasis on distance distribution restraints obtained from electron paramagnetic resonance experiments on spin‐labelled proteins and nucleic acids.
Abstract: Structural characterization of proteins and their complexes may require integration of restraints from various experimental techniques. MMM (Multiscale Modeling of Macromolecules) is a Matlab-based open-source modeling toolbox for this purpose with a particular emphasis on distance distribution restraints obtained from electron paramagnetic resonance experiments on spin-labelled proteins and nucleic acids and their combination with atomistic structures of domains or whole protomers, small-angle scattering data, secondary structure information, homology information, and elastic network models. MMM does not only integrate various types of restraints, but also various existing modeling tools by providing a common graphical user interface to them. The types of restraints that can support such modeling and the available model types are illustrated by recent application examples.

Journal ArticleDOI
TL;DR: In this paper, the authors studied compactifications of the 6d E-string theory to 4-dimensional Riemann surfaces with punctures and with arbitrary non-abelian flat connections as well as fluxes for the abelian subgroups of the E_8 flavor symmetry.
Abstract: We study compactifications of the 6d E-string theory, the theory of a small E_8 instanton, to four dimensions. In particular we identify N=1 field theories in four dimensions corresponding to compactifications on arbitrary Riemann surfaces with punctures and with arbitrary non-abelian flat connections as well as fluxes for the abelian sub-groups of the E_8 flavor symmetry. This sheds light on emergent symmetries in a number of 4d N=1 SCFTs (including the `E7 surprise' theory) as well as leads to new predictions for a large number of 4-dimensional exceptional dualities and symmetries.

Journal ArticleDOI
TL;DR: This work describes how this parametric description for protein modeling can be implemented in an easy‐to‐use web application, called CCBuilder 2.0, for modeling and optimizing both α‐helical coiled coils and polyproline‐based collagen triple helices.
Abstract: The increased availability of user-friendly and accessible computational tools for biomolecular modeling would expand the reach and application of biomolecular engineering and design. For protein modeling, one key challenge is to reduce the complexities of 3D protein folds to sets of parametric equations that nonetheless capture the salient features of these structures accurately. At present, this is possible for a subset of proteins, namely, repeat proteins. The α-helical coiled coil provides one such example, which represents ≈ 3-5% of all known protein-encoding regions of DNA. Coiled coils are bundles of α helices that can be described by a small set of structural parameters. Here we describe how this parametric description can be implemented in an easy-to-use web application, called CCBuilder 2.0, for modeling and optimizing both α-helical coiled coils and polyproline-based collagen triple helices. This has many applications from providing models to aid molecular replacement for X-ray crystallography, in silico model building and engineering of natural and designed protein assemblies, and through to the creation of completely de novo "dark matter" protein structures. CCBuilder 2.0 is available as a web-based application, the code for which is open-source and can be downloaded freely. http://coiledcoils.chm.bris.ac.uk/ccbuilder2. Lay summary We have created CCBuilder 2.0, an easy to use web-based application that can model structures for a whole class of proteins, the α-helical coiled coil, which is estimated to account for 3-5% of all proteins in nature. CCBuilder 2.0 will be of use to a large number of protein scientists engaged in fundamental studies, such as protein structure determination, through to more-applied research including designing and engineering novel proteins that have potential applications in biotechnology.

Journal ArticleDOI
TL;DR: In this article, it was shown that there is no tension between the swampland criteria and the current lower bound on the tensor-to-scalar ratio.
Abstract: We provide some comments about the constraints on the inflationary models inferred from the two Swampland criteria which have been recently proposed. In particular we argue that, in the absence of any knowledge about the origin of the adiabatic curvature perturbations, within the slow-roll single field models of inflation there is no tension between the swampland criteria and the current lower bound on the tensor-to-scalar ratio.

Journal ArticleDOI
TL;DR: The Bsoft software package, developed over 20 years for analyzing electron micrographs, offers a full workflow for validated single particle analysis with extensive functionality, enabling customization for specific cases.
Abstract: Cryo-electron microscopy (cryoEM) is becoming popular as a tool to solve biomolecular structures with the recent availability of direct electron detectors allowing automated acquisition of high resolution data. The Bsoft software package, developed over 20 years for analyzing electron micrographs, offers a full workflow for validated single particle analysis with extensive functionality, enabling customization for specific cases. With the increasing use of cryoEM and its automation, proper validation of the results is a bigger concern. The three major validation approaches, independent data sets, resolution-limited processing, and coherence testing, can be incorporated into any Bsoft workflow. Here, the main workflow is divided into four phases: (i) micrograph preprocessing, (ii) particle picking, (iii) particle alignment and reconstruction, and (iv) interpretation. Each of these phases represents a conceptual unit that can be automated, followed by a check point to assess the results. The aim in the first three phases is to reconstruct one or more validated maps at the best resolution possible. Map interpretation then involves identification of components, segmentation, quantification, and modeling. The algorithms in Bsoft are well established, with future plans focused on ease of use, automation and institutionalizing validation.

Journal ArticleDOI
TL;DR: In this article, the authors studied conformal partial wave (CPW) in Mellin space with totally symmetric external operators of arbitrary integer spin and obtained closed-form expressions for crossing kernels of CPWs in terms of the hypergeometric function 4F3.
Abstract: We study conformal partial waves (CPWs) in Mellin space with totally symmetric external operators of arbitrary integer spin. The exchanged spin is arbitrary, and includes mixed symmetry and (partially)‐conserved representations. In a basis of CPWs recently introduced in arXiv:1702.08619, we find a remarkable factorisation of the external spin dependence in their Mellin representation. This property allows a relatively straightforward study of inversion formulae to extract OPE data from the Mellin representation of spinning 4pt correlators and in particular, to extract closed‐form expressions for crossing kernels of spinning CPWs in terms of the hypergeometric function 4F3. We consider numerous examples involving both arbitrary internal and external spins, and for both leading and sub‐leading twist operators. As an application, working in general d we extract new results for anomalous dimensions of double‐trace operators induced by double‐trace deformations constructed from single‐trace operators of generic twist and integer spin. In particular, we extract the anomalous dimensions of double‐trace operators with a single‐trace operator of integer spin J.

Journal ArticleDOI
TL;DR: The Integrative Modeling Platform (IMP) as mentioned in this paper is an open source software suite for integrative structure modeling, which casts the building of structural models as a computational optimization problem, for which information about the assembly is encoded into a scoring function that evaluates candidate models.
Abstract: Building models of a biological system that are consistent with the myriad data available is one of the key challenges in biology. Modeling the structure and dynamics of macromolecular assemblies, for example, can give insights into how biological systems work, evolved, might be controlled, and even designed. Integrative structure modeling casts the building of structural models as a computational optimization problem, for which information about the assembly is encoded into a scoring function that evaluates candidate models. Here, we describe our open source software suite for integrative structure modeling, Integrative Modeling Platform (IMP) (https://integrativemodeling.org), and demonstrate its use. This article is protected by copyright. All rights reserved.

Journal ArticleDOI
TL;DR: An in‐depth functional comparison of two variants of a family AA9 LPMO from Thermoascus aurantiacus showed that the methylated variant of TaLPMO9A was more resistant to excess H2O2 and showed better process performance when using conditions that promote generation of reactive‐oxygen species.
Abstract: The catalytically crucial N-terminal histidine (His1) of fungal lytic polysaccharide monooxygenases (LPMOs) is post-translationally modified to carry a methylation. The functional role of this methylation remains unknown. We have carried out an in-depth functional comparison of two variants of a family AA9 LPMO from Thermoascus aurantiacus (TaLPMO9A), one with, and one without the methylation on His1. Various activity assays showed that the two enzyme variants are identical in terms of substrate preferences, cleavage specificities and the ability to activate molecular oxygen. During the course of this work, new functional features of TaLPMO9A were discovered, in particular the ability to cleave xyloglucan, and these features were identical for both variants. Using a variety of techniques, we further found that methylation has minimal effects on the pKa of His1, the affinity for copper and the redox potential of bound copper. The two LPMOs did, however, show clear differences in their resistance against oxidative damage. Studies with added hydrogen peroxide confirmed recent claims that low concentrations of H2 O2 boost LPMO activity, whereas excess H2 O2 leads to LPMO inactivation. The methylated variant of TaLPMO9A, produced in Aspergillus oryzae, was more resistant to excess H2 O2 and showed better process performance when using conditions that promote generation of reactive-oxygen species. LPMOs need to protect themselves from reactive oxygen species generated in their active sites and this study shows that methylation of the fully conserved N-terminal histidine provides such protection.

Journal ArticleDOI
TL;DR: This review describes the structure of TFIIH and its roles in pol II initiation, promoter‐proximal pausing, elongation, and termination, and discusses cellular roles forTFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TF IIH and diseases associated with defects in TFIIh structure and function.
Abstract: TFIIH is a 10-subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in eukaryotic cells, much progress has been made even in just the past few years, due in part to technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH and its roles in pol II initiation, promoter-proximal pausing, elongation, and termination. We also discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function.

Journal ArticleDOI
TL;DR: RADDOSE‐3D, a software tool allowing the estimation of the dose absorbed in a macromolecular crystallography diffraction experiment, is presented, giving a universal “x‐axis” against which to plot various metrics.
Abstract: We present the current status of RADDOSE-3D, a software tool allowing the estimation of the dose absorbed in a macromolecular crystallography diffraction experiment. The code allows a temporal and spatial dose contour map to be calculated for a crystal of any geometry and size as it is rotated in an X-ray beam, and gives several summary dose values: among them diffraction weighted dose. This allows experimenters to plan data collections which will minimize radiation damage effects by spreading the absorbed dose more homogeneously, and thus to optimize the use of their crystals. It also allows quantitative comparisons between different radiation damage studies, giving a universal "x-axis" against which to plot various metrics.

Journal ArticleDOI
TL;DR: The results corroborate the previous studies showing that sonication of prion and Aβ fibrils leads to the formation of toxic, soluble aggregates and show that the oligomeric forms are the most toxic species although it is unclear how sonication causes oligomer formation.
Abstract: Several studies have proposed that fibrillary aggregates of tau and other amyloidogenic proteins are neurotoxic and result in numerous neurodegenerative diseases. However, these studies usually involve sonication or extrusion through needles before experimentation. As a consequence, these methods may fragment large aggregates producing a mixture of aggregated species rather than intact fibrils. Therefore, the results of these experiments may be reflective of other amyloidogenic species, such as oligomers and/or protofibrils/short fibrils. To investigate the effects of sonication on the aggregation of tau and other amyloidogenic proteins, fibrils were prepared and well characterized, then sonicated and evaluated by various biochemical and biophysical methods to identify the aggregated species present. We found that indeed a mixture of aggregated species was present along with short fibrils indicating that sonication leads to impure fibril samples and should be analyzed with caution. Our results corroborate the previous studies showing that sonication of prion and Aβ fibrils leads to the formation of toxic, soluble aggregates. We also show that the oligomeric forms are the most toxic species although it is unclear how sonication causes oligomer formation. Recent results suggest that these small toxic oligomers produced by sonication, rather than the stable fibrillar structures, are prion-like in nature displaying seeding and cross-seeding behavior.

Journal ArticleDOI
TL;DR: The new RDB PDBj Mine 2, the WebGL molecular viewer Molmil, the ProMode‐Elastic server for normal mode analysis, a virtual reality system for the eF‐site protein electrostatic molecular surfaces, the extensions of the Omokage search for molecular shape similarity, and the integration of PDBJ and BMRB searches are reported.
Abstract: The Protein Data Bank Japan (PDBj), a member of the worldwide Protein Data Bank (wwPDB), accepts and processes the deposited data of experimentally determined biological macromolecular structures. In addition to archiving the PDB data in collaboration with the other wwPDB partners, PDBj also provides a wide range of original and unique services and tools, which are continuously improved and updated. Here, we report the new RDB PDBj Mine 2, the WebGL molecular viewer Molmil, the ProMode-Elastic server for normal mode analysis, a virtual reality system for the eF-site protein electrostatic molecular surfaces, the extensions of the Omokage search for molecular shape similarity, and the integration of PDBj and BMRB searches.


Journal ArticleDOI
TL;DR: CDtoolX as mentioned in this paper is a free software program that enables processing, displaying, archiving, calibrating, comparisons, and analyses of CD and synchrotron radiation circular dichroism spectroscopic data.
Abstract: Circular dichroism (CD) spectroscopy is a highly used method for the examination and characterization of proteins, including, amongst other features, their secondary and tertiary structures, thermal stability, comparisons of wildtype and mutant proteins, and monitoring the binding of small molecules, folding/unfolding pathways, and formation of macromolecular complexes. This article describes CDtoolX, a new, user-friendly, free-to-download-and-use software program that enables processing, displaying, archiving, calibrating, comparisons, and analyses of CD and synchrotron radiation circular dichroism spectroscopic data.

Journal ArticleDOI
TL;DR: A comprehensive description of the Dockground resource is presented, including previously unpublished unbound docking benchmark set 4, and the X‐ray docking decoy set 2, for structural modeling of protein interactions.
Abstract: Characterization of life processes at the molecular level requires structural details of protein interactions. The number of experimentally determined structures of protein-protein complexes accounts only for a fraction of known protein interactions. This gap in structural description of the interactome has to be bridged by modeling. An essential part of the development of structural modeling/docking techniques for protein interactions is databases of protein-protein complexes. They are necessary for studying protein interfaces, providing a knowledge base for docking algorithms, and developing intermolecular potentials, search procedures, and scoring functions. Development of protein-protein docking techniques requires thorough benchmarking of different parts of the docking protocols on carefully curated sets of protein-protein complexes. We present a comprehensive description of the Dockground resource (http://dockground.compbio.ku.edu) for structural modeling of protein interactions, including previously unpublished unbound docking benchmark set 4, and the X-ray docking decoy set 2. The resource offers a variety of interconnected datasets of protein-protein complexes and other data for the development and testing of different aspects of protein docking methodologies. Based on protein-protein complexes extracted from the PDB biounit files, Dockground offers sets of X-ray unbound, simulated unbound, model, and docking decoy structures. All datasets are freely available for download, as a whole or selecting specific structures, through a user-friendly interface on one integrated website.

Journal ArticleDOI
TL;DR: Among the possible superalgebras that contain the AdS3 isometries, two interesting possibilities are the exceptional F (4) and G(3).
Abstract: Among the possible superalgebras that contain the AdS3 isometries, two interesting possibilities are the exceptional F (4) and G(3). Their R-symmetry is respectively SO(7) and G(2), and the amount ...