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The Molecular Mechanism of P2Y 1 Receptor Activation
Author(s) -
Yuan Shuguang,
Chan H. C. Stephen,
Vogel Horst,
Filipek Slawomir,
Stevens Raymond C.,
Palczewski Krzysztof
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201605147
Subject(s) - p2y receptor , chemistry , biophysics , g protein coupled receptor , purinergic receptor , ligand (biochemistry) , platelet activation , helix (gastropod) , receptor , transmembrane domain , stereochemistry , extracellular , p2 receptor , biochemistry , platelet , biology , ecology , snail , immunology
Human purinergic G protein‐coupled receptor P2Y 1 (P2Y 1 R) is activated by adenosine 5′‐diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y 1 R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 μs all‐atom long‐timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y 1 R activation.