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In silico refinement of a computer model of GPR55, a cannabinoid receptor

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

Abstract: Cannabinoid receptors have great therapeutic potential and are important targets in drug discovery. As part of a broader project whose long-term goal is the determination of the basis for the actions of cannabinoids at the molecular level, this research project focuses on increasing the knowledge of the newly discovered third cannabinoid receptor, GPR55, through computer simulations by refining the model of the inactive (R) state of GPR55. In order to explore the conformational space available to specific transmembrane helices (TMHs) of GPR55, the Conformational Memories (CM), a computational method was used. CM is a Monte Carlo/Simulated Annealing (MC/SA) algorithm that can employ different molecular force fields. In the first part of this work the force field employed and the starting structure used were varied in order to optimize the method. This was done by exploring the conformational space of the second transmembrane helix (TMH2) of CB2, for which experimental data was available for validation. The GPR55 sequence exhibits many of the key sequence motifs of the Class A GPCRs and can therefore be easily aligned with other Class A GPCR sequences. From this alignment possible flexible regions of amino acids on each helix were identified for exploration. The regions were: VLSLP in TMH2, KVFFP, GFLLP, MGIMG in TMH5, VSFLP in TMH6, and CCLDV in TMH7. The calculated conformational space available to these helices is of special importance when building the computer model of GPR55 so that the resultant model reflects the sequence dictated conformation of the receptor bundle. At the beginning of this project, rhodopsin (Rho), the prototype receptor of Class A GPCRs, was the only transmembrane protein for which the crystal structure has been solved. For this reason and because GPR55 has sufficiently sequence similarity with Rho, this receptor was used as a template to build an initial model presented in a poster at the 2006 International Cannabinoid Research Society meeting. The results revealed differences between the conformational tendencies of GPR55 TMHs compared to the template. In the case of the TMH2 population, most helices reached over towards TMH3 more than rhodopsin, while TMH5 bends away from the template regardless of which flexible region was varied. The results of TMH6 conformational memories showed that this population leaned toward the TMH5 at the extracellular end. The present work deepens our understanding of the structure of GPR55 and the conformational differences between it and Rho that are dictated by divergences in amino acid sequence.

Additional Information

Publication
Thesis
Language: English
Date: 2011
Keywords
Cannabinoids, Conformational memories, G-protein coupled receptors
Subjects
Cannabinoids $x Receptors
Cannabinoids $x Structure