Lys39-Lysophosphatidate Carbonyl Oxygen Interaction Locks LPA1 N-terminal Cap to the Orthosteric Site and Partners Arg124 During Receptor Activation

Overview

Journal Sci Rep

Specialty Science

Date 2015 Aug 14

PMID 26268898

Citations 9

Authors

Olaposi I Omotuyi

Jun Nagai

Hiroshi Ueda

Affiliations

Soon will be listed here.

Abstract

Lysophosphatidic acid (LPA) receptor 1 (LPA1) is a member of the G protein-coupled receptors mediating the biological response to LPA species. Lack of detailed mechanism underlying LPA/LPA1 interaction has hampered the development of specific antagonists. Here, novel N-terminal Lys39 has been identified as a key residue during LPA-type agonist binding and LPA1 activation. Analysis of the molecular dynamics (MD) trajectories showed that LPA-type agonist but not VPC-32183 (antagonist) evolved structures with classical GPCR activation signatures such as reduced cytoplasmic transmembrane (TM) 3/TM6 dynamic network, ruptured ionic lock, and formation of a continuous and highly ordered internal water pathway was also observed. In activated state, LPA-type agonists interact with Arg124 (R3.28), Gln125 (Q3.29), Lys294 (K7.36) and a novel N-terminal Lys39. Site-directed mutagenesis showed complete loss of intracellular calcium mobilization in B103 cells expressing R3.28A and Lys39Ala when treated with LPA-type agonists. Structurally, LPA-type agonist via Carbonyl-oxygen/Lys39 interaction facilitated the formation of a hypothetical N-terminal cap tightly packed over LPA1 heptahelical bundle. This packing may represent a key mechanism to distinguish an apo-receptor from bound LPA1.

Citing Articles

Benzimidazole compound abrogates SARS-COV-2 receptor-binding domain (RBD)/ACE2 interaction In vitro.

Omotuyi O, Olatunji O, Nash O, Oyinloye B, Soremekun O, Ijagbuji A Microb Pathog. 2023; 176:105994.

PMID: 36682669 PMC: 9851952. DOI: 10.1016/j.micpath.2023.105994.

Structure of the active G-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist.

Akasaka H, Tanaka T, Sano F, Matsuzaki Y, Shihoya W, Nureki O Nat Commun. 2022; 13(1):5417.

PMID: 36109516 PMC: 9477835. DOI: 10.1038/s41467-022-33121-2.

SARS-CoV-2 Omicron spike glycoprotein receptor binding domain exhibits super-binder ability with ACE2 but not convalescent monoclonal antibody.

Omotuyi O, Olubiyi O, Nash O, Afolabi E, Oyinloye B, Fatumo S Comput Biol Med. 2022; 142:105226.

PMID: 35066447 PMC: 8739363. DOI: 10.1016/j.compbiomed.2022.105226.

Lysophosphatidic Acid Signaling in Cancer Cells: What Makes LPA So Special?.

Balijepalli P, Sitton C, Meier K Cells. 2021; 10(8).

PMID: 34440828 PMC: 8394178. DOI: 10.3390/cells10082059.

Atomistic simulation reveals structural mechanisms underlying D614G spike glycoprotein-enhanced fitness in SARS-COV-2.

Omotuyi I, Nash O, Ajiboye O, Iwegbulam C, Oyinloye E, Oyedeji O J Comput Chem. 2020; 41(24):2158-2161.

PMID: 32779780 PMC: 7404873. DOI: 10.1002/jcc.26383.

References

Takuwa Y, Takuwa N, Sugimoto N . The Edg family G protein-coupled receptors for lysophospholipids: their signaling properties and biological activities. J Biochem. 2002; 131(6):767-71. DOI: 10.1093/oxfordjournals.jbchem.a003163. View

Sevier C, Kaiser C . Formation and transfer of disulphide bonds in living cells. Nat Rev Mol Cell Biol. 2002; 3(11):836-47. DOI: 10.1038/nrm954. View

Ohta H, Sato K, Murata N, Damirin A, Malchinkhuu E, Kon J . Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors. Mol Pharmacol. 2003; 64(4):994-1005. DOI: 10.1124/mol.64.4.994. View

Hilal-Dandan R, Means C, Gustafsson A, Morissette M, Adams J, Brunton L . Lysophosphatidic acid induces hypertrophy of neonatal cardiac myocytes via activation of Gi and Rho. J Mol Cell Cardiol. 2004; 36(4):481-93. DOI: 10.1016/j.yjmcc.2003.12.010. View

McAllister S, Hurst D, Barnett-Norris J, Lynch D, Reggio P, Abood M . Structural mimicry in class A G protein-coupled receptor rotamer toggle switches: the importance of the F3.36(201)/W6.48(357) interaction in cannabinoid CB1 receptor activation. J Biol Chem. 2004; 279(46):48024-37. DOI: 10.1074/jbc.M406648200. View

Fujiwara Y, Sardar V, Tokumura A, Baker D, Murakami-Murofushi K, Parrill A . Identification of residues responsible for ligand recognition and regioisomeric selectivity of lysophosphatidic acid receptors expressed in mammalian cells. J Biol Chem. 2005; 280(41):35038-50. DOI: 10.1074/jbc.M504351200. View

van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark A, Berendsen H . GROMACS: fast, flexible, and free. J Comput Chem. 2005; 26(16):1701-18. DOI: 10.1002/jcc.20291. View

Lomize M, Lomize A, Pogozheva I, Mosberg H . OPM: orientations of proteins in membranes database. Bioinformatics. 2006; 22(5):623-5. DOI: 10.1093/bioinformatics/btk023. View

Guo R, Kasbohm E, Arora P, Sample C, Baban B, Sud N . Expression and function of lysophosphatidic acid LPA1 receptor in prostate cancer cells. Endocrinology. 2006; 147(10):4883-92. DOI: 10.1210/en.2005-1635. View

10.

Chen J, Chen Y, Zhu W, Han Y, Han B, Xu R . Specific LPA receptor subtype mediation of LPA-induced hypertrophy of cardiac myocytes and involvement of Akt and NFkappaB signal pathways. J Cell Biochem. 2007; 103(6):1718-31. DOI: 10.1002/jcb.21564. View

11.

Inoue M, Ma L, Aoki J, Chun J, Ueda H . Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA), mediates the induction of nerve-injured neuropathic pain. Mol Pain. 2008; 4:6. PMC: 2277392. DOI: 10.1186/1744-8069-4-6. View

12.

Valentine W, Fells J, Perygin D, Mujahid S, Yokoyama K, Fujiwara Y . Subtype-specific residues involved in ligand activation of the endothelial differentiation gene family lysophosphatidic acid receptors. J Biol Chem. 2008; 283(18):12175-87. PMC: 3774115. DOI: 10.1074/jbc.M708847200. View

13.

Jo S, Kim T, Iyer V, Im W . CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comput Chem. 2008; 29(11):1859-65. DOI: 10.1002/jcc.20945. View

14.

Sethi A, Eargle J, Black A, Luthey-Schulten Z . Dynamical networks in tRNA:protein complexes. Proc Natl Acad Sci U S A. 2009; 106(16):6620-5. PMC: 2672494. DOI: 10.1073/pnas.0810961106. View

15.

Williams J, Khandoga A, Goyal P, Fells J, Perygin D, Siess W . Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation. J Biol Chem. 2009; 284(25):17304-17319. PMC: 2719366. DOI: 10.1074/jbc.M109.003194. View

16.

Rosenbaum D, Rasmussen S, Kobilka B . The structure and function of G-protein-coupled receptors. Nature. 2009; 459(7245):356-63. PMC: 3967846. DOI: 10.1038/nature08144. View

17.

Hofmann K, Scheerer P, Hildebrand P, Choe H, Park J, Heck M . A G protein-coupled receptor at work: the rhodopsin model. Trends Biochem Sci. 2009; 34(11):540-52. DOI: 10.1016/j.tibs.2009.07.005. View

18.

Choi J, Herr D, Noguchi K, Yung Y, Lee C, Mutoh T . LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol. 2010; 50:157-86. DOI: 10.1146/annurev.pharmtox.010909.105753. View

19.

Bourgoin S, Zhao C . Autotaxin and lysophospholipids in rheumatoid arthritis. Curr Opin Investig Drugs. 2010; 11(5):515-26. View

20.

Swaney J, Chapman C, Correa L, Stebbins K, Bundey R, Prodanovich P . A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br J Pharmacol. 2010; 160(7):1699-713. PMC: 2936842. DOI: 10.1111/j.1476-5381.2010.00828.x. View