Recently we predicted the 3D structure of the human 2-adrenergic receptor (2AR) and of the binding site of several agonists and antagonists to 2AR. These predictions (MembStruk and HierDock) included no explicit water and only a few lipid molecules. Here we include explicit H2O and an infinite lipid bilayer membrane in molecular dynamics (MD) simulations of three systems: apo-2AR, epinephrine-bound 2AR, and butoxamine-bound 2AR (epinephrine is an endogenous agonist, and butoxamine is a 2AR selective antagonist). The predicted structures for apo-2AR and butoxamine-2AR are stable in MD, but in epinephrine-2AR, extracellular water trickles into the binding pocket to mediate hydrogen bonding between the catechol of epinephrine and Ser-204 on helix 5. The epinephrine-2AR structure shows dynamic flexibility with small, piston-like movements of helices 3 and 6 and transient interhelical hydrogen bonding between Ser-165 on transmembrane 4 and Ser-207 on transmembrane 5. These couplings and motions may play a role in protein activation. The apo-2AR shows less dynamic flexibility, whereas the antagonist-2AR structure is quite rigid. This MD validation of the structure predictions for G protein-coupled receptors in explicit lipid and water suggests that these methods can be trusted for studying the mechanism of activation and the design of subtype-specific agonists and antagonists.
|Journal||Proceedings of the National Academy of Sciences of the United States of America (PNAS)|
|Publication status||Published - 2006|