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First Principles Predictions of the Structure and Function of G-Protein-Coupled Receptors: Validation for Bovine Rhodopsin

Trabanino, Rene J. and Hall, Spencer E. and Vaidehi, Nagarajan and Floriano, Wely B. and Kam, Victor W. T. and Goddard, William A., 3rd (2004) First Principles Predictions of the Structure and Function of G-Protein-Coupled Receptors: Validation for Bovine Rhodopsin. Biophysical Journal, 86 (4). pp. 1904-1921. ISSN 0006-3495. PMCID PMC1304048. doi:10.1016/s0006-3495(04)74256-3. https://resolver.caltech.edu/CaltechAUTHORS:20190301-092706690

[img] PDF (Figure S1: The sequences (43 Blast entries shown) used to generate the multiple sequence alignment with bovine rhodopsin) - Supplemental Material
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Abstract

G-protein-coupled receptors (GPCRs) are involved in cell communication processes and with mediating such senses as vision, smell, taste, and pain. They constitute a prominent superfamily of drug targets, but an atomic-level structure is available for only one GPCR, bovine rhodopsin, making it difficult to use structure-based methods to design receptor-specific drugs. We have developed the MembStruk first principles computational method for predicting the three-dimensional structure of GPCRs. In this article we validate the MembStruk procedure by comparing its predictions with the high-resolution crystal structure of bovine rhodopsin. The crystal structure of bovine rhodopsin has the second extracellular (EC-II) loop closed over the transmembrane regions by making a disulfide linkage between Cys-110 and Cys-187, but we speculate that opening this loop may play a role in the activation process of the receptor through the cysteine linkage with helix 3. Consequently we predicted two structures for bovine rhodopsin from the primary sequence (with no input from the crystal structure)—one with the EC-II loop closed as in the crystal structure, and the other with the EC-II loop open. The MembStruk-predicted structure of bovine rhodopsin with the closed EC-II loop deviates from the crystal by 2.84 Å coordinate root mean-square (CRMS) in the transmembrane region main-chain atoms. The predicted three-dimensional structures for other GPCRs can be validated only by predicting binding sites and energies for various ligands. For such predictions we developed the HierDock first principles computational method. We validate HierDock by predicting the binding site of 11-cis-retinal in the crystal structure of bovine rhodopsin. Scanning the whole protein without using any prior knowledge of the binding site, we find that the best scoring conformation in rhodopsin is 1.1 Å CRMS from the crystal structure for the ligand atoms. This predicted conformation has the carbonyl O only 2.82 Å from the N of Lys-296. Making this Schiff base bond and minimizing leads to a final conformation only 0.62 Å CRMS from the crystal structure. We also used HierDock to predict the binding site of 11-cis-retinal in the MembStruk-predicted structure of bovine rhodopsin (closed loop). Scanning the whole protein structure leads to a structure in which the carbonyl O is only 2.85 Å from the N of Lys-296. Making this Schiff base bond and minimizing leads to a final conformation only 2.92 Å CRMS from the crystal structure. The good agreement of the ab initio-predicted protein structures and ligand binding site with experiment validates the use of the MembStruk and HierDock first principles’ methods. Since these methods are generic and applicable to any GPCR, they should be useful in predicting the structures of other GPCRs and the binding site of ligands to these proteins.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/s0006-3495(04)74256-3DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1304048/PubMed CentralArticle
ORCID:
AuthorORCID
Goddard, William A., 3rd0000-0003-0097-5716
Additional Information:© 2004 The Biophysical Society. Under an Elsevier user license. Received 8 September 2003, Accepted 14 November 2003. This research was supported partially by National Institutes of Health grants BRGRO1-GM625523, R29AI40567, and HD365385. The computational facilities were provided by a Shared University Research 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
NIHHD365385
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:4
PubMed Central ID:PMC1304048
DOI:10.1016/s0006-3495(04)74256-3
Record Number:CaltechAUTHORS:20190301-092706690
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190301-092706690
Official Citation:Rene J. Trabanino, Spencer E. Hall, Nagarajan Vaidehi, Wely B. Floriano, Victor W.T. Kam, William A. Goddard, First Principles Predictions of the Structure and Function of G-Protein-Coupled Receptors: Validation for Bovine Rhodopsin, Biophysical Journal, Volume 86, Issue 4, 2004, Pages 1904-1921, ISSN 0006-3495, https://doi.org/10.1016/S0006-3495(04)74256-3. (http://www.sciencedirect.com/science/article/pii/S0006349504742563)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:93387
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:01 Mar 2019 18:09
Last Modified:16 Nov 2021 16:57

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