Human P2Y(6) Receptor: Molecular Modeling Leads to the Rational Design of a Novel Agonist Based on a Unique Conformational Preference

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2005 Dec 22

PMID 16366591

Citations 37

Authors

Stefano Costanzi

Bhalchandra V Joshi

Savitri Maddileti

Liaman Mamedova

Maria J Gonzalez-Moa

Victor E Marquez

T Kendall Harden

Kenneth A Jacobson

Affiliations

Soon will be listed here.

Abstract

Combining molecular dynamics (MD) in a hydrated phospholipid (DOPC) bilayer, a Monte Carlo search, and synthesis of locked nucleotide analogues, we discovered that the Southern conformation of the ribose is preferred for ligand recognition by the P2Y(6) receptor. 2'-Deoxy-(S)-methanocarbaUDP was found to be a full agonist of the receptor and displayed a 10-fold higher potency than that for the corresponding flexible 2'-deoxyUDP. MD results also suggested a conformational change of the second extracellular loop consequent to agonist binding.

Citing Articles

Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y.

Zimmermann A, Vu O, Bruser A, Sliwoski G, Marnett L, Meiler J ChemMedChem. 2022; 17(7):e202100683.

PMID: 35034430 PMC: 9305961. DOI: 10.1002/cmdc.202100683.

A promising drug candidate for the treatment of glaucoma based on a P2Y6-receptor agonist.

Jacob T, Singh V, Dixit M, Ginsburg-Shmuel T, Fonseca B, Pintor J Purinergic Signal. 2018; 14(3):271-284.

PMID: 30019187 PMC: 6107468. DOI: 10.1007/s11302-018-9614-7.

Pyrimidine Nucleotides Containing a (S)-Methanocarba Ring as P2Y Receptor Agonists.

Toti K, Jain S, Ciancetta A, Balasubramanian R, Chakraborty S, Surujdin R Medchemcomm. 2018; 8(10):1897-1908.

PMID: 29423136 PMC: 5798474. DOI: 10.1039/C7MD00397H.

Thymidine 5'-O-monophosphorothioate induces HeLa cell migration by activation of the P2Y6 receptor.

Gendaszewska-Darmach E, Szustak M Purinergic Signal. 2016; 12(2):199-209.

PMID: 26746211 PMC: 4854834. DOI: 10.1007/s11302-015-9492-1.

4-Alkyloxyimino-cytosine nucleotides: tethering approaches to molecular probes for the P2Y receptor.

Jayasekara P, Barrett M, Ball C, Brown K, Kozma E, Costanzi S Medchemcomm. 2015; 4:1156-1165.

PMID: 26161252 PMC: 4493932. DOI: 10.1039/C3MD00132F.

References

Jacobson K, Ji X, Li A, Melman N, Siddiqui M, Shin K . Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists. J Med Chem. 2000; 43(11):2196-203. PMC: 3471159. DOI: 10.1021/jm9905965. View

Kim H, Ravi R, Marquez V, Maddileti S, Wihlborg A, Erlinge D . Methanocarba modification of uracil and adenine nucleotides: high potency of Northern ring conformation at P2Y1, P2Y2, P2Y4, and P2Y11 but not P2Y6 receptors. J Med Chem. 2002; 45(1):208-18. PMC: 4957029. DOI: 10.1021/jm010369e. View

Boyer J, Adams M, Ravi R, Jacobson K, Harden T . 2-Chloro N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate is a selective high affinity P2Y(1) receptor antagonist. Br J Pharmacol. 2002; 135(8):2004-10. PMC: 1573330. DOI: 10.1038/sj.bjp.0704673. View

Ohno M, Costanzi S, Kim H, Kempeneers V, Vastmans K, Herdewijn P . Nucleotide analogues containing 2-oxa-bicyclo[2.2.1]heptane and l-alpha-threofuranosyl ring systems: interactions with P2Y receptors. Bioorg Med Chem. 2004; 12(21):5619-30. PMC: 3402881. DOI: 10.1016/j.bmc.2004.07.067. View

Costanzi S, Mamedova L, Gao Z, Jacobson K . Architecture of P2Y nucleotide receptors: structural comparison based on sequence analysis, mutagenesis, and homology modeling. J Med Chem. 2004; 47(22):5393-404. PMC: 3431558. DOI: 10.1021/jm049914c. View

Woolf T, Roux B . Structure, energetics, and dynamics of lipid-protein interactions: A molecular dynamics study of the gramicidin A channel in a DMPC bilayer. Proteins. 1996; 24(1):92-114. DOI: 10.1002/(SICI)1097-0134(199601)24:1<92::AID-PROT7>3.0.CO;2-Q. View

Marquez V, Siddiqui M, Ezzitouni A, Russ P, Wang J, Wagner R . Nucleosides with a twist. Can fixed forms of sugar ring pucker influence biological activity in nucleosides and oligonucleotides?. J Med Chem. 1996; 39(19):3739-47. DOI: 10.1021/jm960306+. View

Jiang Q, Guo D, Lee B, Van Rhee A, Kim Y, Nicholas R . A mutational analysis of residues essential for ligand recognition at the human P2Y1 receptor. Mol Pharmacol. 1997; 52(3):499-507. PMC: 3425637. DOI: 10.1124/mol.52.3.499. View

Moro S, Hoffmann C, Jacobson K . Role of the extracellular loops of G protein-coupled receptors in ligand recognition: a molecular modeling study of the human P2Y1 receptor. Biochemistry. 1999; 38(12):3498-507. PMC: 4969012. DOI: 10.1021/bi982369v. View

10.

Hoffmann C, Moro S, Nicholas R, Harden T, Jacobson K . The role of amino acids in extracellular loops of the human P2Y1 receptor in surface expression and activation processes. J Biol Chem. 1999; 274(21):14639-47. PMC: 3449168. DOI: 10.1074/jbc.274.21.14639. View

11.

Klco J, Wiegand C, Narzinski K, Baranski T . Essential role for the second extracellular loop in C5a receptor activation. Nat Struct Mol Biol. 2005; 12(4):320-6. DOI: 10.1038/nsmb913. View

12.

Boeynaems J, Communi D, Gonzalez N, Robaye B . Overview of the P2 receptors. Semin Thromb Hemost. 2005; 31(2):139-49. DOI: 10.1055/s-2005-869519. View

13.

Baneres J, Mesnier D, Martin A, Joubert L, Dumuis A, Bockaert J . Molecular characterization of a purified 5-HT4 receptor: a structural basis for drug efficacy. J Biol Chem. 2005; 280(21):20253-60. DOI: 10.1074/jbc.M412009200. View

14.

Schreiber R, Kunzelmann K . Purinergic P2Y6 receptors induce Ca2+ and CFTR dependent Cl- secretion in mouse trachea. Cell Physiol Biochem. 2005; 16(1-3):99-108. DOI: 10.1159/000087736. View

15.

Costanzi S, Vincenzetti S, Cristalli G, Vita A . Human cytidine deaminase: a three-dimensional homology model of a tetrameric metallo-enzyme inferred from the crystal structure of a distantly related dimeric homologue. J Mol Graph Model. 2005; 25(1):10-6. DOI: 10.1016/j.jmgm.2005.10.008. View