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Predicted 3D structure for the human β2 adrenergic receptor and its binding site for agonists and antagonists

Freddolino, Peter L. and Kalani, M. Yashar S. and Vaidehi, Nagarajan and Floriano, Wely B. and Hall, Spencer E. and Trabanino, Rene J. and Kam, Victor Wai Tak and Goddard, William A., III (2004) Predicted 3D structure for the human β2 adrenergic receptor and its binding site for agonists and antagonists. Proceedings of the National Academy of Sciences of the United States of America, 101 (9). pp. 2736-2741. ISSN 0027-8424. PMCID PMC365690. doi:10.1073/pnas.0308751101. https://resolver.caltech.edu/CaltechAUTHORS:20141120-150243775

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Abstract

We report the 3D structure of human β2 adrenergic receptor (AR) predicted by using the MembStruk first principles method. To validate this structure, we use the HierDock first principles method to predict the ligand-binding sites for epinephrine and norepinephrine and for eight other ligands, including agonists and antagonists to β2 AR and ligands not observed to bind to β2 AR. The binding sites agree well with available mutagenesis data, and the calculated relative binding energies correlate reasonably with measured binding affinities. In addition, we find characteristic differences in the predicted binding sites of known agonists and antagonists that allow us to infer the likely activity of other ligands. The predicted ligand-binding properties validate the methods used to predict the 3D structure and function. This validation is a successful step toward applying these procedures to predict the 3D structures and function of the other eight subtypes of ARs, which should enable the development of subtype-specific antagonists and agonists with reduced side effects.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.0308751101DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC365690/PubMed CentralArticle
ORCID:
AuthorORCID
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2004 The National Academy of Sciences. Contributed by William A. Goddard III, January 5, 2004 This research was supported partially by National Institutes of Health Grants BRGRO1-GM625523, R29AI40567, and HD36385. The computational facilities were provided by a Shared UniversityResearch grant from IBM and Defense University Research Instrumentation Program grants from the Army Research Office (ARO) and the Office of Naval Research (ONR). The facilities of the Materials and Process Simulation Center are also supported by the Department of Energy, the National Science Foundation, the Multidisciplinary University Research Initiative (MURI)-ARO, MURI-ONR, General Motors, ChevronTexaco, Seiko-Epson, the Beckman Institute, and Asahi Kasei.
Funders:
Funding AgencyGrant Number
NIHBRGRO1-GM625523
NIHR29AI40567
NIHHD36385
IBMUNSPECIFIED
Army Research Office (ARO)UNSPECIFIED
Office of Naval Research (ONR)UNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
NSFUNSPECIFIED
General MotorsUNSPECIFIED
ChevronTexacoUNSPECIFIED
Seiko-EpsonUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Asahi KaseiUNSPECIFIED
Issue or Number:9
PubMed Central ID:PMC365690
DOI:10.1073/pnas.0308751101
Record Number:CaltechAUTHORS:20141120-150243775
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20141120-150243775
Official Citation:Freddolino, P. L., Kalani, M. Y. S., Vaidehi, N., Floriano, W. B., Hall, S. E., Trabanino, R. J., . . . Goddard, W. A. (2004). Predicted 3D structure for the human β2 adrenergic receptor and its binding site for agonists and antagonists. Proceedings of the National Academy of Sciences of the United States of America, 101(9), 2736-2741. doi: 10.1073/pnas.0308751101
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:52018
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:24 Nov 2014 21:31
Last Modified:10 Nov 2021 19:19

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