title: Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1.
abstract: Lipid biology continues to emerge as an area of significant therapeutic interest, particularly as the result of an enhanced understanding of the wealth of signaling molecules with diverse physiological properties. This growth in knowledge is epitomized by lysophosphatidic acid (LPA), which functions through interactions with at least six cognate G protein-coupled receptors. Herein, we present three crystal structures of LPA1 in complex with antagonist tool compounds selected and designed through structural and stability analyses. Structural analysis combined with molecular dynamics identified a basis for ligand access to the LPA1 binding pocket from the extracellular space contrasting with the proposed access for the sphingosine 1-phosphate receptor. Characteristics of the LPA1 binding pocket raise the possibility of promiscuous ligand recognition of phosphorylated endocannabinoids. Cell-based assays confirmed this hypothesis, linking the distinct receptor systems through metabolically related ligands with potential functional and therapeutic implications for treatment of disease.
authors.affiliation: Department of Structural Discovery, Receptos, San Diego, CA 92121, USA.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Chrencik
authors.affiliation: Department of Structural Discovery, Receptos, San Diego, CA 92121, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Roth
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Terakado
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan.
authors.forename: Haruto
authors.initials: H
authors.lastname: Kurata
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Omi
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kihara
authors.affiliation: Schrödinger Inc., 120 West 45th Street, New York, NY 10036, USA.
authors.forename: Dora
authors.initials: D
authors.lastname: Warshaviak
authors.affiliation: Exploratory Research Laboratories, Ono Pharmaceutical Co., Ltd., Ibaraki 300-4247, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakade
authors.affiliation: Department of Structural Discovery, Receptos, San Diego, CA 92121, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Asmar-Rovira
authors.affiliation: Department of Structural Discovery, Receptos, San Diego, CA 92121, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Mileni
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Exploratory Research Laboratories, Ono Pharmaceutical Co., Ltd., Ibaraki 300-4247, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Mizuno
authors.affiliation: Department of Structural Discovery, Receptos, San Diego, CA 92121, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Griffith
authors.affiliation: Department of Structural Discovery, Receptos, San Diego, CA 92121, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rodgers
authors.affiliation: Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, Los Angeles, CA 90089, USA.
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.affiliation: Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, Los Angeles, CA 90089, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Velasquez
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, Los Angeles, CA 90089, USA; iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai, 201210, China.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.affiliation: Department of Structural Discovery, Receptos, San Diego, CA 92121, USA. Electronic address: mhanson@gpcrconsortium.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hanson
mesh_terms: D001665:Binding Sites; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors; D049349:Receptors, Lysosphingolipid / Q000737:chemistry; D054852:Small Molecule Libraries
chemical_list: D008024:Ligands; D049368:Receptors, Lysophosphatidic Acid; D049349:Receptors, Lysosphingolipid; D054852:Small Molecule Libraries