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P2Y 1 ‐like nucleotide receptors—Structures, molecular modeling, mutagenesis, and oligomerization
Author(s) -
Neumann Alexander,
Müller Christa E.,
Namasivayam Vigneshwaran
Publication year - 2020
Publication title -
wiley interdisciplinary reviews: computational molecular science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.126
H-Index - 81
eISSN - 1759-0884
pISSN - 1759-0876
DOI - 10.1002/wcms.1464
Subject(s) - p2y receptor , g protein coupled receptor , nucleotide , receptor , homology modeling , agonist , transmembrane domain , mutant , site directed mutagenesis , chemistry , biochemistry , biology , stereochemistry , gene , enzyme
The P2Y receptors (P2YRs) are G protein‐coupled receptors (GPCRs) consisting of eight members, subdivided into two groups, P2Y 1 ‐ and P2Y 12 ‐like receptor subtypes. They are activated by extracellular nucleotides and represent current (P2Y 2 , P2Y 12 ) or potential future drug targets. The chemical nature of the highly polar endogenous agonists represents a challenge in the discovery and design of potent and bioavailable compounds. A number of mutants and several homology models of P2YR subtypes have been created and updated on the basis of the recently published X‐ray crystal structures of the human P2Y 1 and P2Y 12 Rs. The models were used for prediction of the binding sites of agonists and antagonists, and mutants were constructed for confirmation. Pharmacological data on mutants published for the P2Y 1 ‐like receptors (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 R) were evaluated to analyze the role of specific amino acids and that of corresponding amino acid residues in related P2Y receptor subtypes. In several P2YR subtypes, an ionic lock between extracellular loop 2 and transmembrane region VII was postulated to be essential for agonist‐induced receptor activation. Mutagenesis and homology modeling data suggest that the nucleotide antagonist (1′ R ,2′ S ,4′ S ,5′ S )‐4‐(2‐iodo‐6‐methylaminopurin‐9‐yl)‐1‐[(phosphato)methyl]‐2‐(phosphato)bicyclo[3.1.0]hexane (MRS2500), which was co‐crystallized with the human P2Y 1 R, binds differently from agonistic nucleotides to a site partly overlapping with that of orthosteric agonists. Hetero‐oligomerization of P2YRs with other P2YR subtypes or other GPCRs may allosterically modulate receptor‐ligand interactions and/or G protein coupling. The collected information will contribute to the understanding of the architecture of P2Y 1 ‐like nucleotide receptors and will consequently be useful for the design of novel agonists and antagonists. This article is categorized under: Molecular and Statistical Mechanics > Free Energy Methods Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Interactions Software > Molecular Modeling