4Z36

Crystal Structure of Human Lysophosphatidic Acid Receptor 1 in complex with ONO-3080573

Summary for 4Z36

• Entry DOI: 10.2210/pdb4z36/pdb
• Related: 4Z34 4Z35
• Descriptor: Lysophosphatidic acid receptor 1,Soluble cytochrome b562, 1-(4-{[(2S,3R)-2-(2,3-dihydro-1H-inden-2-yloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl]oxy}phenyl)cyclopropan ecarboxylic acid, (2S)-2,3-dihydroxypropyl (7Z)-tetradec-7-enoate, ... (4 entities in total)
• Functional Keywords: human lysophosphatidic acid receptor 1 (lpa1), g-protein coupled receptor (gpcr), membrane protein, antagonist, endogenous ligand, psi-biology, structural genomics, gpcr network, lipidic cubic phase (lcp), novel disulfide bond engineering, compound design, polypharmacology, lipid receptor, transport protein-inhibitor complex, transport protein/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell surface : Q92633
• Total number of polymer chains: 1
• Total formula weight: 52661.36

Authors

Chrencik, J.E.,Roth, C.B.,Terakado, M.,Kurata, H.,Omi, R.,Kihara, Y.,Warshaviak, D.,Nakade, S.,Asmar-Rovira, G.,Mileni, M.,Mizuno, H.,Griffith, M.T.,Rodgers, C.,Han, G.W.,Velasquez, J.,Chun, J.,Stevens, R.C.,Hanson, M.A.,GPCR Network (GPCR) (deposition date: 2015-03-30, release date: 2015-06-03, Last modification date: 2024-11-13)

Primary citation

Chrencik, J.E.,Roth, C.B.,Terakado, M.,Kurata, H.,Omi, R.,Kihara, Y.,Warshaviak, D.,Nakade, S.,Asmar-Rovira, G.,Mileni, M.,Mizuno, H.,Griffith, M.T.,Rodgers, C.,Han, G.W.,Velasquez, J.,Chun, J.,Stevens, R.C.,Hanson, M.A.
Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1.
Cell, 161:1633-1643, 2015

PubMed 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.

PubMed: 26091040
DOI: 10.1016/j.cell.2015.06.002

Experimental method

X-RAY DIFFRACTION (2.9 Å)