title: The Molecular Mechanism of P2Y1 Receptor Activation.
abstract: Human purinergic G protein-coupled receptor P2Y1 (P2Y1 R) is activated by adenosine 5'-diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1 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 P2Y1 R activation.
authors.affiliation: Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. shuguang.yuan@gmail.com.
authors.forename: Shuguang
authors.identifier: 0000-0001-9858-4742
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Faculty of Life Sciences, University of Bradford, Bradford, UK.
authors.forename: H C Stephen
authors.initials: HC
authors.lastname: Chan
authors.affiliation: Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Horst
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Laboratory of Biomodeling, Faculty of Chemistry & Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Filipek
authors.affiliation: iHuman Institute, Shanghai Technical University, China and, Departments of Biological Sciences and Chemistry, University of Southern California, USA. stevens@usc.edu.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, USA. kxp65@case.edu.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D058472:Receptors, Purinergic P2Y1 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D058472:Receptors, Purinergic P2Y1
keywords: GPCR; P2Y1R; activation mechanism; allosteric ligand; molecular switches