title: 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.
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry (C.L.P., X.D.), and Condensed Matter Theory Group, Department of Research with Neutrons and Muons (X.D.), Paul Scherrer Institute, Villigen, Switzerland; Heptares Therapeutics Ltd., Welwyn Garden City, United Kingdom (J.K.); and Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems, VU University of Amsterdam, Amsterdam, The Netherlands (C.G.).
authors.forename: Chayne L
authors.initials: CL
authors.lastname: Piscitelli
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry (C.L.P., X.D.), and Condensed Matter Theory Group, Department of Research with Neutrons and Muons (X.D.), Paul Scherrer Institute, Villigen, Switzerland; Heptares Therapeutics Ltd., Welwyn Garden City, United Kingdom (J.K.); and Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems, VU University of Amsterdam, Amsterdam, The Netherlands (C.G.).
authors.forename: James
authors.initials: J
authors.lastname: Kean
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry (C.L.P., X.D.), and Condensed Matter Theory Group, Department of Research with Neutrons and Muons (X.D.), Paul Scherrer Institute, Villigen, Switzerland; Heptares Therapeutics Ltd., Welwyn Garden City, United Kingdom (J.K.); and Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems, VU University of Amsterdam, Amsterdam, The Netherlands (C.G.).
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry (C.L.P., X.D.), and Condensed Matter Theory Group, Department of Research with Neutrons and Muons (X.D.), Paul Scherrer Institute, Villigen, Switzerland; Heptares Therapeutics Ltd., Welwyn Garden City, United Kingdom (J.K.); and Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems, VU University of Amsterdam, Amsterdam, The Netherlands (C.G.) xavier.deupi@psi.ch c.de.graaf@vu.nl.
authors.forename: Xavier
authors.initials: X
authors.lastname: Deupi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray / Q000379:methods*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled