Home
This Title All WIREs
WIREs RSS Feed
How to cite this WIREs title:
WIREs Comput Mol Sci
Impact Factor: 16.778

P2Y1‐like nucleotide receptors—Structures, molecular modeling, mutagenesis, and oligomerization

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

Abstract The P2Y receptors (P2YRs) are G protein‐coupled receptors (GPCRs) consisting of eight members, subdivided into two groups, P2Y1‐ and P2Y12‐like receptor subtypes. They are activated by extracellular nucleotides and represent current (P2Y2, P2Y12) 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 P2Y1 and P2Y12Rs. 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 P2Y1‐like receptors (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11R) 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 P2Y1R, 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 P2Y1‐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
Sequence alignment of the human P2Y1‐like receptor subtypes. Residues important for agonist‐induced receptor activation predicted by MD simulations are highlighted in blue. Amino acid residues mutated in more than one receptor subtype are highlighted in red. Multiple sequence alignment was generated using Clustal Omega. MD, molecular dynamics
[ Normal View | Magnified View ]
Structures of selected P2Y12R antagonists and A1AR agonists and antagonists
[ Normal View | Magnified View ]
Structures of selected P2YR antagonists
[ Normal View | Magnified View ]
Structures of selected P2YR antagonists
[ Normal View | Magnified View ]
Structures of selected (proposed) P2Y receptor agonists
[ Normal View | Magnified View ]
Schematic presentation of P2YRs embedded in a phospholipid bilayer and their preferred endogenous agonists. A phylogenetic tree shows the degree of their relationship. The endogenous agonists activating the respective receptor at physiologically relevant concentrations and the G protein coupling are shown at the top. Phylogenetic analysis was generated using Clustal Omega
[ Normal View | Magnified View ]
Oligomerization of P2Y receptors. (a) Oligomerization of P2Y1R with P2Y11R and the resulting impact on the pharmacological profile of the P2Y11R. (b) Dimerization of P2Y1R and P2Y12R modulates the responses of the receptors toward K2P ion channels when coexpressed in the same cell line. The profile of the dimers is similar to the pharmacological profile of the P2Y12R, while the G protein‐coupling seems to be comparable to that of the P2Y1R. Oligomerization of the adenosine A1 receptor with the P2Y1R (c) and the P2Y2R (d). The oligomeric A1AR/P2YR exhibits a preference for the corresponding P2YR agonists, whereas the potency of A1AR agonist and agonists is reduced
[ Normal View | Magnified View ]
Overlay of the agonist‐bound X‐ray crystal structures of the human P2Y12R, the nucleotide antagonist‐bound X‐ray crystal structure of human P2Y1R, as well as the proposed binding mode of UTP in complex with the homology model of human P2Y2R. The P2Y12R complex with the agonist 2‐MeSADP is colored in yellow, the P2Y12R complex with agonist 2‐MeSATP is colored in red, the P2Y1R complex with antagonist MRS2500 (2.2) is colored in blue, the homology model P2Y2R complex with agonist UTP is colored in green. The ligands are shown as stick models and the carbon atoms are colored respective to their receptor. Nitrogen atoms are colored in blue, oxygen in red, phosphorus in orange, sulfur in yellow. The β‐ and γ‐phosphate groups of the UTP bind close to a region occupied by the 5′‐phosphate group of the P2Y1 antagonist MRS2500 (2.2)
[ Normal View | Magnified View ]
Overlay of RB‐2 (2.9) and the smaller anthraquinone derivative PSB‐16133 (2.14) in complex with the homology model of the human P2Y4R. The receptor is presented in cartoon style. The helices are colored in red, the extracellular loops in green, and the β‐sheet of ECL2 in yellow. The antagonists are presented as stick models. RB‐2 is colored in blue, the smaller, most potent anthraquinone derivative PSB‐16133 is colored in orange
[ Normal View | Magnified View ]
Comparison of residues between ECL2 and TMVII which might play a role in receptor activation. P2Y1R data was taken from the X‐ray crystal structure (PDB‐ID: 4XNW), P2Y2R and P2Y4R data from published homology models based on the P2Y1R structure. The ionic lock could be induced by rotamer library selection. Ionic contact is presented by dashed lines
[ Normal View | Magnified View ]
Cartoon‐style presentation of published X‐ray crystal structures of P2YRs and their respective PDB‐ID. On the left side, both of the antagonist‐bound structures of the human P2Y1R are shown in complex with 2.02 (MRS2500, PDB‐ID.: 4XNW) in light blue, and with 2.05 (BPTU, PDB‐ID: 4XNV) in violet blue. On the right side, the three available structures of the P2Y12R are shown: in red the complex with the agonist 2‐MeSADP (2‐MeSADP, PDB‐ID: 4PXZ), in yellow the complex with the agonist 2‐MeSATP (1.07, PDB‐ID: 4PY0), and in orange the complex with a competitive antagonist 3.05 (AZD1283, PDB‐ID: 4NTJ). The receptors are presented as cartoon models, the co‐crystallized atoms of the ligands are presented as spheres: carbon atoms are colored in white, nitrogen atoms in blue, oxygen atoms in red, phosphorus atoms in orange, sulfur atoms in yellow, iodine atoms in purple
[ Normal View | Magnified View ]
Schematic presentation of mutated residues in the human P2Y2R homology model based on the human P2Y1R X‐ray crystal structure. Transmembrane regions are presented as cylinders. Mutations of residues highlighted in red led to a large decrease in potency or complete abolishment of the receptor's ability to be activated by agonists. Mutation of green colored residues had a moderate impact on agonist potency. Purple‐colored mutants led to a decrease in potency only for ATP
[ Normal View | Magnified View ]
Schematic tree diagram of available mutagenesis data for agonist and antagonist potencies of the human P2Y2R
[ Normal View | Magnified View ]
Schematic presentation of mutated residues depicted in the X‐ray crystal structure of the human P2Y1R (PDB: 4XNW). Transmembrane regions are presented as cylinders. Roman numbers indicate the transmembrane regions. Mutations of residues highlighted in red led to a large decrease in potency or complete abolishment of the receptor's ability to be activated by agonists. Mutation of green colored residues had no or low impact on agonist potency. Blue highlighted residues were shown to participate in the binding of different antagonists
[ Normal View | Magnified View ]
Schematic diagram of available mutagenesis data of the human P2Y1R, and effects of mutations on agonist and antagonist potencies. High impact was defined as at least 10‐fold change in the potency of the agonist. Changes below a 10‐fold difference in potency of the agonist were defined as low impact
[ Normal View | Magnified View ]

Browse by Topic

Software > Molecular Modeling
Molecular and Statistical Mechanics > Molecular Interactions
Structure and Mechanism > Computational Biochemistry and Biophysics
Molecular and Statistical Mechanics > Free Energy Methods

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts