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Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1. 2015

Jill E Chrencik, and Christopher B Roth, and Masahiko Terakado, and Haruto Kurata, and Rie Omi, and Yasuyuki Kihara, and Dora Warshaviak, and Shinji Nakade, and Guillermo Asmar-Rovira, and Mauro Mileni, and Hirotaka Mizuno, and Mark T Griffith, and Caroline Rodgers, and Gye Won Han, and Jeffrey Velasquez, and Jerold Chun, and Raymond C Stevens, and Michael A Hanson
Department of Structural Discovery, Receptos, San Diego, CA 92121, USA.

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.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D002850 Chromatography, Gel Chromatography on non-ionic gels without regard to the mechanism of solute discrimination. Chromatography, Exclusion,Chromatography, Gel Permeation,Chromatography, Molecular Sieve,Gel Filtration,Gel Filtration Chromatography,Chromatography, Size Exclusion,Exclusion Chromatography,Gel Chromatography,Gel Permeation Chromatography,Molecular Sieve Chromatography,Chromatography, Gel Filtration,Exclusion Chromatography, Size,Filtration Chromatography, Gel,Filtration, Gel,Sieve Chromatography, Molecular,Size Exclusion Chromatography
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D049349 Receptors, Lysosphingolipid A subfamily of lysophospholipid receptors with specificity for LYSOSPHINGOLIPIDS such as sphingosine-1-phosphate and sphingosine phosphorylcholine. Lysosphingolipid Receptors,Lysosphingolipid Receptor,Receptor, Lysosphingolipid
D049368 Receptors, Lysophosphatidic Acid A subfamily of lysophospholipid receptors with specificity for LYSOPHOSPHATIDIC ACIDS. LPA Receptor,Lysophosphatidic Acid Receptor,Lysophosphatidic Acid Receptors,EDG7 Protein,Edg-4 Receptor,Edg-7 Receptor,Edg2 Protein,Edg4 Protein,LPA Receptors,LPA-1 Receptor,LPA1 Receptor,LPA2 Receptor,LPA3 Receptor,Receptor, Lysophosphatidic Acid,edg-2 Receptor,vzg-1 Receptor,Acid Receptor, Lysophosphatidic,Acid Receptors, Lysophosphatidic,Edg 4 Receptor,Edg 7 Receptor,LPA 1 Receptor,Receptor, Edg-4,Receptor, Edg-7,Receptor, LPA,Receptor, LPA1,Receptor, LPA2,Receptor, LPA3,Receptor, edg-2,Receptor, vzg-1,Receptors, LPA,edg 2 Receptor,vzg 1 Receptor
D054852 Small Molecule Libraries Large collections of small molecules (molecular weight about 600 or less), of similar or diverse nature which are used for high-throughput screening analysis of the gene function, protein interaction, cellular processing, biochemical pathways, or other chemical interactions. It includes virtual libraries. Chemical Libraries,Molecular Libraries, Small,Libraries, Chemical,Libraries, Small Molecular,Libraries, Small Molecule,Molecule Libraries, Small,Small Molecular Libraries
D018360 Crystallography, X-Ray The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) X-Ray Crystallography,Crystallography, X Ray,Crystallography, Xray,X Ray Crystallography,Xray Crystallography,Crystallographies, X Ray,X Ray Crystallographies

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