The Molecular Mechanism of P2Y1 Receptor Activation |
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| Authors: | Dr. Shuguang Yuan Dr. H. C. Stephen Chan Prof. Horst Vogel Prof. Slawomir Filipek Prof. Raymond C. Stevens Prof. Krzysztof Palczewski |
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| Affiliation: | 1. Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland;2. Faculty of Life Sciences, University of Bradford, Bradford, UK;3. Laboratory of Biomodeling, Faculty of Chemistry & Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland;4. iHuman Institute, Shanghai Technical University, China and, Departments of Biological Sciences and Chemistry, University of Southern California, USA;5. Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, USA |
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| Abstract: | Human purinergic G protein‐coupled receptor P2Y1 (P2Y1R) is activated by adenosine 5′‐diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1R 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 P2Y1R activation. |
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| Keywords: | activation mechanism allosteric ligand GPCR molecular switches P2Y1R |
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