Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol Sci

Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 01/2012; 33(1):17-27. DOI: 10.1016/
Source: PubMed

ABSTRACT G protein-coupled receptors (GPCRs) comprise the most 'prolific' family of cell membrane proteins, which share a general mechanism of signal transduction, but greatly vary in ligand recognition and function. Crystal structures are now available for rhodopsin, adrenergic, and adenosine receptors in both inactive and activated forms, as well as for chemokine, dopamine, and histamine receptors in inactive conformations. Here we review common structural features, outline the scope of structural diversity of GPCRs at different levels of homology, and briefly discuss the impact of the structures on drug discovery. Given the current set of GPCR crystal structures, a distinct modularity is now being observed between the extracellular (ligand-binding) and intracellular (signaling) regions. The rapidly expanding repertoire of GPCR structures provides a solid framework for experimental and molecular modeling studies, and helps to chart a roadmap for comprehensive structural coverage of the whole superfamily and an understanding of GPCR biological and therapeutic mechanisms.

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    • "In this study, helix VI and helix VII were found to move independently, providing a physical basis for biased agonism and a conformational "signature" predictive of arrestin selectivity. Although to date there is little direct X-ray crystallographic structure of GPCRs bound to conventional and biased agonist ligands, computational modeling of agonist docking within the ligand binding pocket of family A GPCRs suggests that efficacy correlates with engagement of certain residues and exclusion of interaction with others (Katritch et al., 2012; Jacobson and Costanzi, 2012; Costanzi, 2014). Historically, the experimental hallmark of orthosteric ligand bias has been "reversal of potency," where two ligands exhibit opposite rank order of potency for two downstream responses measured in the same system (Sagan et al., 1996; Berg et al., 1998; Takasu et al., 1999), or "reversal of efficacy," where a single ligand exhibits opposing efficacy toward two "
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    • "An understanding of the function of a membrane receptor starts with determination of its structure and the nature of its ligand-binding site. Impressive advances have been made in the last decade in membrane protein expression and purification resulting in the use of X-ray crystallography on membrane protein crystals of G protein-coupled receptors (GPCRs) to elucidate overall structure, and in some cases, an atomic-level image of the ligand-binding site (Bortolato et al., 2014; Cherezov et al., 2007; Chien et al., 2010; Chung et al., 2011; Hanson & Stevens, 2009; Jaakola et al., 2008; Katritch, Cherezov, & Stevens, 2012; Rasmussen et al., 2011; Scheerer et al., 2009; Warne et al., 2008, 2011; Wu et al., 2010, 2014). Approximately, 360 genes encode members of a human membrane protein family composed of nonolfactory GPCRs (Fredriksson, Lagerstrom, Lundin, & Schioth, 2003). "
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    ABSTRACT: Experiments are described that allowed cross-linking of analogs of a 13-amino acid peptide into the binding site of a model G protein-coupled receptor. Syntheses of peptide analogs that were used for photochemical or chemical cross-linking were carried out using solid-phase peptide synthesis. Chemical cross-linking utilized 3,4-dihydroxy-l-phenylalanine-incorporated peptides and subsequent periodate-mediated activation, whereas photochemical cross-linking was mediated by p-benzoyl-l-phenylalanine (Bpa)-labeled peptides and UV-initiated activation. Mass spectrometry was employed to locate the site(s) in the receptor that formed the cross-links to the ligand. We also describe a method called unnatural amino acid replacement that allowed capture of a peptide ligand into the receptor. In this method, the receptor was genetically modified by replacement of a natural amino acid with Bpa. The modified receptor was UV-irradiated to capture the ligand. The approaches described are applicable to other peptide-binding proteins and can reveal the ligand-binding site in atomic detail. © 2015 Elsevier Inc. All rights reserved.
    Methods in enzymology 04/2015; 556:527-47. DOI:10.1016/bs.mie.2014.12.001 · 2.09 Impact Factor
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    • "This apparent discrepancy has been partially explained by the fact that, in crystal structures, ICL3 has a propensity in some receptors for forming a-helical structures which elongate the helices 5 and 6, causing variations in transmembrane domain length (Park et al. 2008; Moukhametzianov et al. 2011; Katritch et al. 2012). These structural features may have important signalling consequences, as ICL3 is believed to control receptor selectivity to different G proteins (Katritch et al. 2012). Moreover, the functional activities of several residues conserved among MCRs have been investigated in various mutagenesis experiments. "
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