Integrating structural and mutagenesis data to elucidate GPCR ligand binding.

G protein-coupled receptors (GPCRs) represent the largest family of human membrane proteins, as well as drug targets. A recent boom in GPCR structural biology has provided detailed images of receptor ligand binding sites and interactions on the molecular level. An ever-increasing number of ligands is reported that exhibit activity through multiple receptors, binding in allosteric sites, and bias towards different intracellular signalling pathways. Furthermore, a wealth of single point mutants has accumulated in literature and public databases. Integrating these structural and mutagenesis data will help elucidate new GPCR ligand binding sites, and ultimately design drugs with tailored pharmacological activity.

[1]  Chris de Graaf,et al.  Generic GPCR residue numbers - aligning topology maps while minding the gaps. , 2015, Trends in pharmacological sciences.

[2]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[3]  S. P. Andrews,et al.  Extra-helical binding site of a glucagon receptor antagonist , 2016, Nature.

[4]  Angela D. Wilkins,et al.  Determinants of Endogenous Ligand Specificity Divergence among Metabotropic Glutamate Receptors* , 2014, The Journal of Biological Chemistry.

[5]  R. Stevens,et al.  Crystal structure-based virtual screening for fragment-like ligands of the human histamine H(1) receptor. , 2011, Journal of medicinal chemistry.

[6]  J. Wess,et al.  Activation and allosteric modulation of a muscarinic acetylcholine receptor , 2013, Nature.

[7]  Charles L. Brooks,et al.  Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008 , 2009, Nature Reviews Drug Discovery.

[8]  Avner Schlessinger,et al.  Ligand Discovery from a Dopamine D3 Receptor Homology Model and Crystal Structure , 2011, Nature chemical biology.

[9]  Ruben Abagyan,et al.  Structure of the human histamine H1 receptor complex with doxepin , 2011, Nature.

[10]  D. Gloriam,et al.  Definition of the G protein-coupled receptor transmembrane bundle binding pocket and calculation of receptor similarities for drug design. , 2009, Journal of medicinal chemistry.

[11]  Miles Congreve,et al.  Structure-based drug design for G protein-coupled receptors. , 2014, Progress in medicinal chemistry.

[12]  R. Stevens,et al.  Structure-function of the G protein-coupled receptor superfamily. , 2013, Annual review of pharmacology and toxicology.

[13]  Joanna L. Sharman,et al.  The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands , 2015, Nucleic Acids Res..

[14]  Jonathan S. Mason,et al.  Structures of G protein-coupled receptors reveal new opportunities for drug discovery. , 2015, Drug discovery today.

[15]  O. Lichtarge,et al.  Evolutionary Trace of G Protein-coupled Receptors Reveals Clusters of Residues That Determine Global and Class-specific Functions* , 2004, Journal of Biological Chemistry.

[16]  Øyvind Edvardsen,et al.  tGRAP, the G-protein coupled receptors mutant database , 2002, Nucleic Acids Res..

[17]  Gebhard F. X. Schertler,et al.  The structural basis of agonist-induced activation in constitutively active rhodopsin , 2011, Nature.

[18]  M. Rask-Andersen,et al.  The druggable genome: Evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication. , 2014, Annual review of pharmacology and toxicology.

[19]  O. Lichtarge,et al.  Intramolecular allosteric communication in dopamine D2 receptor revealed by evolutionary amino acid covariation , 2016, Proceedings of the National Academy of Sciences.

[20]  Olivier Lichtarge,et al.  Evolution-guided discovery and recoding of allosteric pathway specificity determinants in psychoactive bioamine receptors , 2010, Proceedings of the National Academy of Sciences.

[21]  Hualiang Jiang,et al.  Two disparate ligand-binding sites in the human P2Y1 receptor , 2015, Nature.

[22]  Vadim Cherezov,et al.  Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs , 2014, Nature Communications.

[23]  David E. Gloriam,et al.  Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors – A Structural Perspective of Ligands and Mutants , 2015, Scientific Reports.

[24]  D. Veprintsev,et al.  Stabilization of G protein-coupled receptors by point mutations , 2015, Front. Pharmacol..

[25]  Gert Vriend,et al.  GPCRDB information system for G protein-coupled receptors , 2003, Nucleic Acids Res..

[26]  Ruben Abagyan,et al.  Advances in GPCR modeling evaluated by the GPCR Dock 2013 assessment: meeting new challenges. , 2014, Structure.

[27]  J. Shiloach,et al.  Structure of the agonist-bound neurotensin receptor , 2012, Nature.

[28]  G. Weiss,et al.  Combinatorial alanine-scanning. , 2001, Current opinion in chemical biology.

[29]  Jianyun Huang,et al.  Crystal Structure of Oligomeric β1-Adrenergic G Protein- Coupled Receptors in Ligand-Free Basal State , 2013, Nature Structural &Molecular Biology.

[30]  Ali Jazayeri,et al.  Structure of class B GPCR corticotropin-releasing factor receptor 1 , 2013, Nature.

[31]  R. Leurs,et al.  Pharmacological modulation of chemokine receptor function , 2012, British journal of pharmacology.

[32]  Peter Mombaerts,et al.  Genes and ligands for odorant, vomeronasal and taste receptors , 2004, Nature Reviews Neuroscience.

[33]  P Kolb,et al.  GPCRdb: the G protein‐coupled receptor database – an introduction , 2016, British journal of pharmacology.

[34]  A. Doré,et al.  Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain , 2014, Nature.

[35]  R. L. Baldwin,et al.  Origin of the different strengths of the (i,i+4) and (i,i+3) leucine pair interactions in helices. , 2002, Biophysical chemistry.

[36]  S. Rasmussen,et al.  Crystal Structure of the β2Adrenergic Receptor-Gs protein complex , 2011, Nature.

[37]  Bas Vroling,et al.  GPCRdb: an information system for G protein-coupled receptors , 2015, Nucleic Acids Res..

[38]  R. Abagyan,et al.  Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists , 2010, Science.

[39]  M. Babu,et al.  Molecular signatures of G-protein-coupled receptors , 2013, Nature.

[40]  Peter Kolb,et al.  Structure-based discovery of β2-adrenergic receptor ligands , 2009, Proceedings of the National Academy of Sciences.

[41]  Kalyan C. Tirupula,et al.  A minimal ligand binding pocket within a network of correlated mutations identified by multiple sequence and structural analysis of G protein coupled receptors , 2012, BMC biophysics.

[42]  Ruben Abagyan,et al.  Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment. , 2011, Structure.

[43]  Jens Meiler,et al.  Structure of a Class C GPCR Metabotropic Glutamate Receptor 1 Bound to an Allosteric Modulator , 2014, Science.

[44]  Nona Naderi,et al.  Automated extraction and semantic analysis of mutation impacts from the biomedical literature , 2012, BMC Genomics.

[45]  Motonori Ota,et al.  The Protein Mutant Database , 1999, Nucleic Acids Res..

[46]  Albert C. Pan,et al.  Pathway and mechanism of drug binding to G-protein-coupled receptors , 2011, Proceedings of the National Academy of Sciences.

[47]  David E. Gloriam,et al.  A new crystal structure fragment-based pharmacophore method for G protein-coupled receptors. , 2015, Methods.

[48]  Kenneth A Jacobson,et al.  Molecular architecture of G protein‐coupled receptors , 1996, Drug development research.

[49]  Bryan L. Roth,et al.  Structure of the human smoothened receptor bound to an antitumour agent , 2013, Nature.

[50]  Garth J. Williams,et al.  Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser , 2014, Nature.

[51]  Benjamin G Tehan,et al.  Unifying family A GPCR theories of activation. , 2014, Pharmacology & therapeutics.