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Structural biology

About: Structural biology is a research topic. Over the lifetime, 2206 publications have been published within this topic receiving 126070 citations.


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Journal ArticleDOI
TL;DR: Advances in cross-linking mass spectrometry technologies indicate that current XL-MS methodologies are ideally positioned to bridge the gap between proteomic-based interactome studies and high-resolution structural biology-based technologies.

101 citations

Journal ArticleDOI
TL;DR: The findings reveal that diverse spatial and structural assemblies mediating GPCR oligomerization may acutely fine-tune the cellular signaling profile.

101 citations

Journal ArticleDOI
TL;DR: Although membrane proteins represent the largest type of drug targets, up to 70% today, determination of their structure has been modest compared to that of soluble proteins, an emphasis has been placed on developing technologies and methods to determine membrane protein structures.
Abstract: Structure-based drug discovery has proven useful in improving and shortening the drug development process. The approach of structural genomics to study a large number of targets in parallel has been commonly applied to protein families and even whole genomes. Paradoxically, although membrane proteins represent the largest type of drug targets, up to 70% today, determination of their structure has been modest compared to that of soluble proteins. Because membrane proteins are important for drug discovery an emphasis has been placed on developing technologies and methods to determine membrane protein structures. Several structural genomics initiatives have been established, focusing on the structural biology of membrane proteins.

101 citations

Journal ArticleDOI
TL;DR: The energy landscape theory is proposed which provides a consistent framework to better understand how a protein folds rapidly and efficiently to the compact, biologically active structure.
Abstract: Protein folding, misfolding and aggregation, as well as the way misfolded and aggregated proteins affects cell viability are emerging as key themes in molecular and structural biology and in molecular medicine. Recent advances in the knowledge of the biophysical basis of protein folding have led to propose the energy landscape theory which provides a consistent framework to better understand how a protein folds rapidly and efficiently to the compact, biologically active structure. The increased knowledge on protein folding has highlighted its strict relation to protein misfolding and aggregation, either process being in close competition with the other, both relying on the same physicochemical basis. The theory has also provided information to better understand the structural and environmental factors affecting protein folding resulting in protein misfolding and aggregation into ordered or disordered polymeric assemblies. Among these, particular importance is given to the effects of surfaces. The latter, in some cases make possible rapid and efficient protein folding but most often recruit proteins/peptides increasing their local concentration thus favouring misfolding and accelerating the rate of nucleation. It is also emerging that surfaces can modify the path of protein misfolding and aggregation generating oligomers and polymers structurally different from those arising in the bulk solution and endowed with different physical properties and cytotoxicities.

101 citations

Journal ArticleDOI
TL;DR: A first illustration of the use of biased combinatorial libraries to discover peptide ligands to proteins resulting in the discovery of novel and specific ligands containing non-peptide structural elements is reported.
Abstract: Small molecule ligands can be used to cause a conditional loss or gain of function of their protein receptors and, therefore, can be viewed as equivalents of conditional alleles.1-3 In order to extend their use, methods to identify such ligands de novo are required. We have previously reported the use of biased combinatorial libraries to discover peptide ligands to proteins,4 and the coupled use of combinatorial chemistry and structural biology to understand the nature of protein-ligand interactions.5-7 More recently, we have been exploring whether the knowledge of protein structure can facilitate the design of monomers and linking elements leading to vast numbers of potential ligands targeted to a particular protein. We now report a first illustration of this strategy resulting in the discovery of novel and specific ligands containing non-peptide structural elements. Structural investigations of SH3-peptide complexes have revealed that SH3 domains bind peptide ligands in either of two orientations (classes I and II; these differ in the directionality of the backbone amides5,6) involving the three pockets depicted in Figure 1.4-7 We designed a library of ligands predisposed to adopt the class I orientation by attaching a common lowaffinity (Kd > 1 mM) biasing sequence PLPPLP (P ) Pro, L ) Leu) to a solid support. This sequence was expected to fill the two pockets (labeled 1 and 2) that bind Leu-Pro dipeptides. Furthermore, structural analyses show that the N-terminal proline should be positioned to orient elements attached to its pyrrolidine nitrogen into the third pocket (labeled 3), which is lined by the nSrc and RT loops common to all SH3 domains and is the primary determinant of ligand specificity.8 We synthesized an encoded9 combinatorial library derived from 32 monomers incorporated during three consecutive cycles of split-and-pool synthesis10,11 following the synthesis of the common PLPPLP sequence (synthesized in the C to N direction) and terminating with one of 32 capping reagents (Figure 2). We purposefully incorporated an encoded blank (“skip-codon”)12 during monomer and cap incorporation in order to increase library diversity significantly by creating sublibraries with deletions at any one or more of the three monomer and one cap sites.

100 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202335
202272
2021149
2020154
2019152
2018140