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W246(6.48) opens a gate for a continuous intrinsic water pathway during activation of the adenosine A2A receptor.
Journal article

W246(6.48) opens a gate for a continuous intrinsic water pathway during activation of the adenosine A2A receptor.

  • Yuan S Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne (Switzerland). shuguang.yuan@gmail.com.
  • Hu Z
  • Filipek S
  • Vogel H
  • 2014-11-19
Published in:
  • Angewandte Chemie (International ed. in English). - 2015
G-protein-coupled receptor
molecular dynamics simulations
molecular switches
signal transduction
water channel
Molecular Dynamics Simulation
Receptor, Adenosine A2A
Water
English The question how G-protein-coupled receptors transduce an extracellular signal by a sequence of transmembrane conformational transitions into an intracellular response remains to be solved at molecular detail. Herein, we use molecular dynamics simulations to reveal distinct conformational transitions of the adenosine A2A receptor, and we found that the conserved W246(6.48) residue in transmembrane helix TM6 performs a key rotamer toggle switch. Agonist binding induces the sidechain of W246(6.48) to fluctuate between two distinct conformations enabling the diffusion of water molecules from the bulk into the center of the receptor. After passing the W246(6.48) gate, the internal water molecules induce another conserved residue, Y288(7.53), to switch to a distinct rotamer conformation establishing a continuous transmembrane water pathway. Further, structural changes of TM6 and TM7 induce local structural changes of the adjacent lipid bilayer.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/99493
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