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Dynamic behavior of fully solvated beta2-adrenergic receptor, embedded in the membrane with bound agonist or antagonist

Spijker, Peter and Vaidehi, Nagarajan and Freddolino, Peter L. and Hilbers, Peter A. J. and Goddard, William A., III (2006) Dynamic behavior of fully solvated beta2-adrenergic receptor, embedded in the membrane with bound agonist or antagonist. Proceedings of the National Academy of Sciences of the United States of America, 103 (13). pp. 4882-4887. ISSN 0027-8424. PMCID PMC1458764.

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Recently we predicted the 3D structure of the human beta2-adrenergic receptor (beta2AR) and of the binding site of several agonists and antagonists to beta2AR. 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-beta2AR, epinephrine-bound beta2AR, and butoxamine-bound beta2AR (epinephrine is an endogenous agonist, and butoxamine is a beta2AR selective antagonist). The predicted structures for apo-beta2AR and butoxamine-beta2AR are stable in MD, but in epinephrine-beta2AR, extracellular water trickles into the binding pocket to mediate hydrogen bonding between the catechol of epinephrine and Ser-204 on helix 5. The epinephrine-beta2AR 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-beta2AR shows less dynamic flexibility, whereas the antagonist-beta2AR 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.

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Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2006 by The National Academy of Sciences of the USA Contributed by William A. Goddard III, January 5, 2006 We thank Drs. Deepshikha Datta, Yashar Kalani, Spencer Hall, and Valeria Molinero for useful input and discussions and Dr. Koen Pieterse for some of the artwork. P.S. is the recipient of a Fulbright Scholarship supported by The Netherland–America Foundation and the Institute of International Education for research performed at the California Institute of Technology. Author contributions: P.S. and N.V. performed research; P.S., N.V., P.L.F., P.A.J.H., and W.A.G. analyzed data; P.S. and W.A.G. wrote the paper; and P.S., N.V., P.L.F., P.A.J.H., and W.A.G. discussed the results and significance. Conflict of interest statement: No conflicts declared.
Funding AgencyGrant Number
Fulbright FoundationUNSPECIFIED
Netherland–America FoundationUNSPECIFIED
Institute of International EducationUNSPECIFIED
Issue or Number:13
PubMed Central ID:PMC1458764
Record Number:CaltechAUTHORS:SPIpnas06
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5969
Deposited By: Archive Administrator
Deposited On:09 Nov 2006
Last Modified:02 Oct 2019 23:28

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