Author
Christopher M. Barbieri
Bio: Christopher M. Barbieri is an academic researcher from Rutgers University. The author has contributed to research in topics: Aminoglycoside & Replication protein A. The author has an hindex of 5, co-authored 5 publications receiving 138 citations.
Papers
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TL;DR: This work has used a combination of biochemical and structural analysis to compare and contrast the molecular mechanisms of action and the structure–activity relationships of a new synthetic aminoglycoside, NB33, and a structurally similar natural aminglycoside apramycin, and demonstrates the general molecular principles that determine the decreased selectivity of apramYcin for the prokaryotic decoding site, and the increased selectivity for NB33.
Abstract: The lack of absolute prokaryotic selectivity of natural antibiotics is widespread and is a significant clinical problem. The use of this disadvantage of aminoglycoside antibiotics for the possible treatment of human genetic diseases is extremely challenging. Here, we have used a combination of biochemical and structural analysis to compare and contrast the molecular mechanisms of action and the structure-activity relationships of a new synthetic aminoglycoside, NB33, and a structurally similar natural aminoglycoside apramycin. The data presented herein demonstrate the general molecular principles that determine the decreased selectivity of apramycin for the prokaryotic decoding site, and the increased selectivity of NB33 for the eukaryotic decoding site. These results are therefore extremely beneficial for further research on both the design of new aminoglycoside-based antibiotics with diminished deleterious effects on humans, as well as the design of new aminoglycoside-based structures that selectively target the eukaryotic ribosome.
57 citations
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TL;DR: This work highlights a new approach for studying minor conformational changes due to structural plasticity within a single dimeric interface in solution, and uses sparse data to limit conformational search during optimization of a physically realistic energy function.
Abstract: Oligomeric proteins are important targets for structure determination in solution. While in most cases the fold of individual subunits can be determined experimentally, or predicted by homology-based methods, protein-protein interfaces are challenging to determine de novo using conventional NMR structure determination protocols. Here we focus on a member of the bet-V1 superfamily, Aha1 from Colwellia psychrerythraea. This family displays a broad range of crystallographic interfaces none of which can be reconciled with the NMR and SAXS data collected for Aha1. Unlike conventional methods relying on a dense network of experimental restraints, the sparse data are used to limit conformational search during optimization of a physically realistic energy function. This work highlights a new approach for studying minor conformational changes due to structural plasticity within a single dimeric interface in solution.
32 citations
01 Jan 2014
TL;DR: In this paper, the authors focus on a member of the bet-V1 superfamily, Aha1 from Colwellia psychrerythraea, and highlight a new approach for studying minor conformational changes due to structural plasticity within a single dimeric interface in solution.
Abstract: Oligomeric proteins are important targets for structure determination in solution. While in most cases the fold of individual subunits can be determined experimentally, or predicted by homology-based methods, protein–protein interfaces are challenging to determine de novo using conventional NMR structure determination protocols. Here we focus on a member of the bet-V1 superfamily, Aha1 from Colwellia psychrerythraea. This family displays a broad range of crystallographic interfaces none of which can be reconciled with the NMR and SAXS data collected for Aha1. Unlike conventional methods relying on a dense network of experimental restraints, the sparse data are used to limit conformational search during optimization of a physically realistic energy function. This work highlights a new approach for studying minor conformational changes due to structural plasticity within a single dimeric interface in solution.
29 citations
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27 Jan 200513 citations
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TL;DR: The molecular function of protein domain family domain of unknown function DUF2128 (PF09901) as a novel ss DNA binding domain is uncovered and this bacterial domain strongly associates into a dimer and presents a highly positively charged surface that is consistent with its function in non-specific ssDNA binding.
Abstract: Single-stranded DNA (ssDNA) binding proteins are important in basal metabolic pathways for gene transcription, recombination, DNA repair and replication in all domains of life. Their main cellular role is to stabilize melted duplex DNA and protect genomic DNA from degradation. We have uncovered the molecular function of protein domain family domain of unknown function DUF2128 (PF09901) as a novel ssDNA binding domain. This bacterial domain strongly associates into a dimer and presents a highly positively charged surface that is consistent with its function in non-specific ssDNA binding. Lactococcus lactis YdbC is a representative of DUF2128. The solution NMR structures of the 20 kDa apo-YdbC dimer and YdbC:dT19G1 complex were determined. The ssDNA-binding energetics to YdbC were characterized by isothermal titration calorimetry. YdbC shows comparable nanomolar affinities for pyrimidine and mixed oligonucleotides, and the affinity is sufficiently strong to disrupt duplex DNA. In addition, YdbC binds with lower affinity to ssRNA, making it a versatile nucleic acid-binding domain. The DUF2128 family is related to the eukaryotic nuclear protein positive cofactor 4 (PC4) family and to the PUR family both by fold similarity and molecular function.
12 citations
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01 Jan 2010
TL;DR: It is found that women over 50 are more likely to have a family history of diabetes, especially if they are obese, than women under the age of 50.
Abstract: Hypertension 66 (20.3%) 24 (24.2%) 30 (16.3%) NS Diabetes 20 (6.2%) 7 (7.1%) 10 (5.4%) NS Excess weight 78 (24%) 27 (27.3%) 44 (23.9%) NS Smokers 64 (19.7%) 17 (17.2%) 35 (19.0%) NS Age >50 years 137 (42.2%) 54 (54.5%) 67 (36.4%) <0.02 Kidney disease 7 (2.2%) 1 (1%) 5 (2.7%) NS Family history, DM 102 (31.4%) 28 (28.3%) 66 (35.9%) NS
1,369 citations
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TL;DR: An overview of coarse-grained models focusing on their design, including choices of representation, models of energy functions, sampling of conformational space, and applications in the modeling of protein structure, dynamics, and interactions are provided.
Abstract: The traditional computational modeling of protein structure, dynamics, and interactions remains difficult for many protein systems. It is mostly due to the size of protein conformational spaces and required simulation time scales that are still too large to be studied in atomistic detail. Lowering the level of protein representation from all-atom to coarse-grained opens up new possibilities for studying protein systems. In this review we provide an overview of coarse-grained models focusing on their design, including choices of representation, models of energy functions, sampling of conformational space, and applications in the modeling of protein structure, dynamics, and interactions. A more detailed description is given for applications of coarse-grained models suitable for efficient combinations with all-atom simulations in multiscale modeling strategies.
711 citations
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New York University1, Johns Hopkins University2, University of Washington3, Duke University4, University of North Carolina at Chapel Hill5, Scripps Research Institute6, Hebrew University of Jerusalem7, Ohio State University8, University of California, San Francisco9, Baylor College of Medicine10, École Polytechnique Fédérale de Lausanne11, Vanderbilt University12, Rutgers University13, Swiss Institute of Bioinformatics14, Fred Hutchinson Cancer Research Center15, Rensselaer Polytechnic Institute16, Northeastern University17, Stanford University18, DSM19, Fox Chase Cancer Center20, University of Maryland, College Park21, University of Warsaw22, University of Denver23, Australian National University24, University of Kansas25, University of Zurich26, University of Massachusetts Dartmouth27, University of Tokyo28, Franklin & Marshall College29, Weizmann Institute of Science30, Lund University31, University of California, Santa Cruz32, University of California, Davis33
TL;DR: This Perspective reviews tools developed over the past five years in the Rosetta software, including over 80 methods, and discusses improvements to the score function, user interfaces and usability.
Abstract: The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities. Here we review tools developed in the last 5 years, including over 80 methods. We discuss improvements to the score function, user interfaces and usability. Rosetta is available at http://www.rosettacommons.org.
430 citations
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TL;DR: Genetic studies of mutants affected in pathways involved in sn-glycerol-3-phosphate metabolism have led to the identification of two additional multidrug tolerance loci, glpABC, the anaerobic sn- Glycerol 3-Phosphate dehydrogenase, and plsB, an sn- glycerol -3- phosphate acyltransferase.
Abstract: Bacterial populations produce dormant persister cells that are resistant to killing by all antibiotics currently in use, a phenomenon known as multidrug tolerance (MDT). Persisters are phenotypic variants of the wild type and are largely responsible for MDT of biofilms and stationary populations. We recently showed that a hipBA toxin/antitoxin locus is part of the MDT mechanism in Escherichia coli. In an effort to find additional MDT genes, an E. coli expression library was selected for increased survival to ampicillin. A clone with increased persister production was isolated and was found to overexpress the gene for the conserved aerobic sn-glycerol-3-phosphate dehydrogenase GlpD. The GlpD overexpression strain showed increased tolerance to ampicillin and ofloxacin, while a strain with glpD deleted had a decreased level of persisters in the stationary state. This suggests that GlpD is a component of the MDT mechanism. Further genetic studies of mutants affected in pathways involved in sn-glycerol-3-phosphate metabolism have led to the identification of two additional multidrug tolerance loci, glpABC, the anaerobic sn-glycerol-3-phosphate dehydrogenase, and plsB, an sn-glycerol-3-phosphate acyltransferase.
205 citations
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TL;DR: This work describes here the first systematic development of the novel aminoglycoside 2 (NB54) exhibiting superior in vitro readthrough efficiency to that of gentamicin in seven different DNA fragments derived from mutant genes carrying nonsense mutations representing the genetic diseases Usher syndrome, cystic fibrosis, Duchenne muscular dystrophy, and Hurler syndrome.
Abstract: Nonsense mutations promote premature translational termination and represent the underlying cause of a large number of human genetic diseases. The aminoglycoside antibiotic gentamicin has the ability to allow the mammalian ribosome to read past a false-stop signal and generate full-length functional proteins. However, severe toxic side effects along with the reduced suppression efficiency at subtoxic doses limit the use of gentamicin for suppression therapy. We describe here the first systematic development of the novel aminoglycoside 2 (NB54) exhibiting superior in vitro readthrough efficiency to that of gentamicin in seven different DNA fragments derived from mutant genes carrying nonsense mutations representing the genetic diseases Usher syndrome, cystic fibrosis, Duchenne muscular dystrophy, and Hurler syndrome. Comparative acute lethal toxicity in mice, cell toxicity, and the assessment of hair cell toxicity in cochlear explants further indicated that 2 exhibits far lower toxicity than that of gentamicin.
188 citations