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3D structural model of the G-protein-coupled cannabinoid CB2 receptor.
Proteins. 2003 Nov 01; 53(2):307-19.P

Abstract

The potential for therapeutic specificity in regulating diseases and for reduced side effects has made cannabinoid (CB) receptors one of the most important G-protein-coupled receptor (GPCR) targets for drug discovery. The cannabinoid (CB) receptor subtype CB2 is of particular interest due to its involvement in signal transduction in the immune system and its increased characterization by mutational and other studies. However, our understanding of their mode of action has been limited by the absence of an experimental receptor structure. In this study, we have developed a 3D model of the CB2 receptor based on the recent crystal structure of a related GPCR, bovine rhodopsin. The model was developed using multiple sequence alignment of homologous receptor sub-types in humans and mammals, and compared with other GPCRs. Alignments were analyzed with mutation scores, pairwise hydrophobicity profiles and Kyte-Doolittle plots. The 3D model of the transmembrane segment was generated by mapping the CB2 sequence onto the homologous residues of the rhodopsin structure. The extra- and intracellular loop regions of the CB2 were generated by searching for homologous C(alpha) backbone sequences in published structures in the Brookhaven Protein Databank (PDB). Residue side chains were positioned through a combination of rotamer library searches, simulated annealing and minimization. Intermediate models of the 7TM helix bundles were analyzed in terms of helix tilt angles, hydrogen-bond networks, conserved residues and motifs, possible disulfide bonds. The amphipathic cytoplasmic helix domain was also correlated with biological and site-directed mutagenesis data. Finally, the model receptor-binding cavity was characterized using solvent-accessible surface approach.

Authors+Show Affiliations

Institute of Materials Science, and Department of Pharmaceutical Science, School of Pharmacy, University of Connecticut, Storrs, Connecticut 06269-3136, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14517981

Citation

Xie, Xiang-Qun, et al. "3D Structural Model of the G-protein-coupled Cannabinoid CB2 Receptor." Proteins, vol. 53, no. 2, 2003, pp. 307-19.
Xie XQ, Chen JZ, Billings EM. 3D structural model of the G-protein-coupled cannabinoid CB2 receptor. Proteins. 2003;53(2):307-19.
Xie, X. Q., Chen, J. Z., & Billings, E. M. (2003). 3D structural model of the G-protein-coupled cannabinoid CB2 receptor. Proteins, 53(2), 307-19.
Xie XQ, Chen JZ, Billings EM. 3D Structural Model of the G-protein-coupled Cannabinoid CB2 Receptor. Proteins. 2003 Nov 1;53(2):307-19. PubMed PMID: 14517981.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3D structural model of the G-protein-coupled cannabinoid CB2 receptor. AU - Xie,Xiang-Qun, AU - Chen,Jian-Zhong, AU - Billings,Eric M, PY - 2003/10/1/pubmed PY - 2004/2/27/medline PY - 2003/10/1/entrez SP - 307 EP - 19 JF - Proteins JO - Proteins VL - 53 IS - 2 N2 - The potential for therapeutic specificity in regulating diseases and for reduced side effects has made cannabinoid (CB) receptors one of the most important G-protein-coupled receptor (GPCR) targets for drug discovery. The cannabinoid (CB) receptor subtype CB2 is of particular interest due to its involvement in signal transduction in the immune system and its increased characterization by mutational and other studies. However, our understanding of their mode of action has been limited by the absence of an experimental receptor structure. In this study, we have developed a 3D model of the CB2 receptor based on the recent crystal structure of a related GPCR, bovine rhodopsin. The model was developed using multiple sequence alignment of homologous receptor sub-types in humans and mammals, and compared with other GPCRs. Alignments were analyzed with mutation scores, pairwise hydrophobicity profiles and Kyte-Doolittle plots. The 3D model of the transmembrane segment was generated by mapping the CB2 sequence onto the homologous residues of the rhodopsin structure. The extra- and intracellular loop regions of the CB2 were generated by searching for homologous C(alpha) backbone sequences in published structures in the Brookhaven Protein Databank (PDB). Residue side chains were positioned through a combination of rotamer library searches, simulated annealing and minimization. Intermediate models of the 7TM helix bundles were analyzed in terms of helix tilt angles, hydrogen-bond networks, conserved residues and motifs, possible disulfide bonds. The amphipathic cytoplasmic helix domain was also correlated with biological and site-directed mutagenesis data. Finally, the model receptor-binding cavity was characterized using solvent-accessible surface approach. SN - 1097-0134 UR - https://www.unboundmedicine.com/medline/citation/14517981/3D_structural_model_of_the_G_protein_coupled_cannabinoid_CB2_receptor_ L2 - https://doi.org/10.1002/prot.10511 DB - PRIME DP - Unbound Medicine ER -