Document Detail


G-protein-coupled receptor structure, ligand binding and activation as studied by solid-state NMR spectroscopy.
MedLine Citation:
PMID:  23445222     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
GPCRs (G-protein-coupled receptors) are versatile signalling molecules at the cell surface and make up the largest and most diverse family of membrane receptors in the human genome. They convert a large variety of extracellular stimuli into intracellular responses through the activation of heterotrimeric G-proteins, which make them key regulatory elements in a broad range of normal and pathological processes, and are therefore one of the most important targets for pharmaceutical drug discovery. Knowledge of a GPCR structure enables us to gain a mechanistic insight into its function and dynamics, and further aid rational drug design. Despite intensive research carried out over the last three decades, resolving the structural basis of GPCR function is still a major activity. The crystal structures obtained in the last 5 years provide the first opportunity to understand how protein structure dictates the unique functional properties of these complex signalling molecules. However, owing to the intrinsic hydrophobicity, flexibility and instability of membrane proteins, it is still a challenge to crystallize GPCRs, and, when this is possible, it is no longer in its native membrane environment and no longer without modification. Furthermore, the conformational change of the transmembrane α-helices associated with the structure activation increases the difficulty of capturing the activation state of a GPCR to a higher resolution by X-ray crystallography. On the other hand, solid-state NMR may offer a unique opportunity to study membrane protein structure, ligand binding and activation at atomic resolution in the native membrane environment, as well as described functionally significant dynamics. In the present review, we discuss some recent achievements of solid-state NMR for understanding GPCRs, the largest mammalian proteome at ~1% of the total expressed proteins. Structural information, details of determination, details of ligand conformations and the consequences of ligand binding to initiate activation can all be explored with solid-state NMR.
Authors:
Xiaoyan Ding; Xin Zhao; Anthony Watts
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  The Biochemical journal     Volume:  450     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-28     Completed Date:  2013-04-17     Revised Date:  2013-05-06    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  443-57     Citation Subset:  IM    
Affiliation:
Shanghai Key Laboratory of Magnetic Resonance, Department of Physics, East China Normal University, Shanghai 200062, PR China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Humans
Ligands
Models, Biological
Models, Molecular
Nuclear Magnetic Resonance, Biomolecular / methods*
Protein Binding
Protein Conformation
Receptors, G-Protein-Coupled / agonists*,  chemistry*,  metabolism*,  physiology
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/Ligands; 0/Receptors, G-Protein-Coupled
Comments/Corrections
Erratum In:
Biochem J. 2013 Apr 15;451(2):343

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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