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Refinement of the conformation of selected transmembrane helices in the cannabinoid receptor GPR55 using conformational memories (CM).

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Karla E. Madrigal (Creator)
Institution
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/
Advisor
Patricia Reggio

Abstract: GPR55 is a newly de-orphanized cannabinoid receptor which belongs to the class A G-protein coupled receptors (GPCRs) family and binds constitutes of the plant, Cannabis sativa. It has been suggested that the manipulation of GPR55 may have a therapeutic potential in the treatment of inflammatory and neuropathic pain. The purpose of the present study was to refine the transmembrane helices (TMH) conformation in GPR55 that have significant sequence divergence from other class A GPCRs. The methods used were conformational memories (CM) to refine the transmembrane helices (TMH) of TMH2, TMH5, TMH6 and TMH7. The results of these calculations were used to modify the GPR55 computer model initially built in Reggio lab based on a rhodopsin template to generate refined inactive and active models of GPR55. The average proline kink angle and standard deviation for each set of conformational results generated by CM were measured using the Prokink program. A statistical analysis of the resultant face shift, wobble angle and bend angle of the helices containing proline was performed using the one sample t test and compared to the β-2 adrenergic receptor. The refined model of the inactive receptor of GPR55 obtained from the conformational memories is shown in figure 1. In conclusion the results of conformational memories are consistent with the proposal of Ballesteros, that even though the overall structure of rhodopsin and other class A GPCRs may be very similar, there are localized regions where the structures of these receptors diverge. A significant range of conformational diversity could be generated by the presence of Pro-kinks and Cys/Ser/Thr residues. The results obtained should help to define the mechanism of drug receptor interaction relevant to cannabinoid physiological and pathophysiological functions including drug abuse.

Additional Information

Publication
Thesis
Language: English
Date: 2011
Keywords
Conformational memories, GPCR modeling, GPR55, Proline, Transmembrane proteins
Subjects
Cannabinoids $x Receptors
Cannabinoids $x Structure