Structural biology

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

Experimental nuclear magnetic resonance studies of membrane proteins.

Abstract: Publisher Summary This chapter presents the major features of an experimental NMR approach for describing membrane proteins based on combining the results of solid-state NMR experiments on oriented and unoriented samples of proteins in hydrated phospholipid bilayers with those from multidimensional solution. NMR spectroscopy has been successfully applied to the study of selected membrane peptides and proteins. Therefore, there is good reason to be optimistic that as the samples and spectroscopic methods are improved, NMR spectroscopy will become generally applicable to membrane proteins. The current status of structural studies of membrane proteins should also be noted. But NMR experiments on samples of proteins in detergent micelles in aqueous solution. Although at an early stage in its development, this approach has been successfully applied to several membrane-associated peptides and proteins. NMR spectroscopy has the potential to open an entire area of structural biology with thorough studies of membrane proteins.

Large-scale discovery of protein interactions at residue resolution using co-evolution calculated from genomic sequences.

Abstract: Increasing numbers of protein interactions have been identified in high-throughput experiments, but only a small proportion have solved structures. Recently, sequence coevolution-based approaches have led to a breakthrough in predicting monomer protein structures and protein interaction interfaces. Here, we address the challenges of large-scale interaction prediction at residue resolution with a fast alignment concatenation method and a probabilistic score for the interaction of residues. Importantly, this method (EVcomplex2) is able to assess the likelihood of a protein interaction, as we show here applied to large-scale experimental datasets where the pairwise interactions are unknown. We predict 504 interactions de novo in the E. coli membrane proteome, including 243 that are newly discovered. While EVcomplex2 does not require available structures, coevolving residue pairs can be used to produce structural models of protein interactions, as done here for membrane complexes including the Flagellar Hook-Filament Junction and the Tol/Pal complex. Our understanding of the residue-level details of protein interactions remains incomplete. Here, the authors show sequence coevolution can be used to infer interacting proteins with residue-level details, including predicting 467 interactions de novo in the Escherichia coli cell envelope proteome.

A Molecular Pharmacologist's Guide to G Protein-Coupled Receptor Crystallography.

Abstract: G protein-coupled receptor (GPCR) structural biology has progressed dramatically in the last decade. There are now over 120 GPCR crystal structures deposited in the Protein Data Bank of 32 different receptors from families scattered across the phylogenetic tree, including class B, C, and Frizzled GPCRs. These structures have been obtained in combination with a wide variety of ligands and captured in a range of conformational states. This surge in structural knowledge has enlightened research into the molecular recognition of biologically active molecules, the mechanisms of receptor activation, the dynamics of functional selectivity, and fueled structure-based drug design efforts for GPCRs. Here we summarize the innovations in both protein engineering/molecular biology and crystallography techniques that have led to these advances in GPCR structural biology and discuss how they may influence the resulting structural models. We also provide a brief molecular pharmacologist's guide to GPCR X-ray crystallography, outlining some key aspects in the process of structure determination, with the goal to encourage noncrystallographers to interrogate structures at the molecular level. Finally, we show how chemogenomics approaches can be used to marry the wealth of existing receptor pharmacology data with the expanding repertoire of structures, providing a deeper understanding of the mechanistic details of GPCR function.

NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors.

Abstract: Transcription factors are proteins that can bind to DNA to regulate the activity of genes One family of transcription factors in mammals is known as the bHLH-PAS family, which consists of sixteen members including NPAS1 and NPAS3 These two proteins are both found in nerve cells, and genetic mutations that affect NPAS1 or NPAS3 have been linked to psychiatric conditions in humans Therefore, researchers would like to discover new drugs that can bind to these proteins and control their activities in nerve cells Understanding the three-dimensional structure of a protein can aid the discovery of small molecules that can bind to these proteins and act as drugs Proteins in the bHLH-PAS family have to form pairs in order to bind to DNA: NPAS1 and NPAS3 both interact with another bHLH-PAS protein called ARNT, but it is not clear exactly how this works In 2015, a team of researchers described the shapes that ARNT adopts when it forms pairs with two other bHLH-PAS proteins that are important for sensing when oxygen levels drop in cells Here, Wu et al – including many of the researchers involved in the earlier work – have used a technique called X-ray crystallography to determine the three-dimensional shapes of NPAS1 when it is bound to ARNT, and NPAS3 when it is bound to both ARNT and DNA The experiments show that each of these structures contains four distinct pockets that certain small molecules might be able to bind to The NPAS1 and NPAS3 structures are similar to each other and to the previously discovered bHLH-PAS structures involved in oxygen sensing Further analysis of other bHLH-PAS proteins suggests that all the members of this protein family are likely to be able to bind to small molecules and should therefore be considered as potential drug targets The next step following on from this work is to identify small molecules that bind to bHLH-PAS proteins, which will help to reveal the genes that are regulated by this family In the future, these small molecules may have the potential to be developed into new drugs to treat psychiatric conditions and other diseases in humans