Abstract
The G-protein coupled receptor 87 (GPR87) is a recently discovered orphan GPCR which means that the search of their endogenous ligands has been a novel challenge. GPR87 has been shown to be overexpressed in squamous cell carcinomas (SCCs) or adenocarcinomas in lungs and bladder. The 3D structure of GPR87 was here modeled using two templates (2VT4 and 2ZIY) by a threading method. Functional assignment of GPR87 by SVM revealed that along with transporter activity, various novel functions were predicted. The 3D structure was further validated by comparison with structural features of the templates through Verify-3D, ProSA and ERRAT for determining correct stereochemical parameters. The resulting model was evaluated by Ramachandran plot and good 3D structure compatibility was evidenced by DOPE score. Molecular dynamics simulation and solvation of protein were studied through explicit spherical boundaries with a harmonic restraint membrane water system. A DRY-motif (Asp-Arg-Tyr sequence) was found at the end of transmembrane helix3, where GPCR binds and thus activation of signals is transduced. In a search for better inhibitors of GPR87, in silico modification of some substrate ligands was carried out to form polar interactions with Arg115 and Lys296. Thus, this study provides early insights into the structure of a major drug target for SCCs.
Highlights
G protein-coupled receptors (GPCRs) are still a large superfamily of membrane bound signaling proteins that hold great pharmaceutical interest as a promising drug target (Costanzi et al, 2012)
The G-protein coupled receptor 87 (GPR87) is a recently discovered orphan GPCR which means that the search of their endogenous ligands has been a novel challenge
GPR87 has been shown to be overexpressed in squamous cell carcinomas (SCCs) or adenocarcinomas in lungs and bladder
Summary
G protein-coupled receptors (GPCRs) are still a large superfamily of membrane bound signaling proteins that hold great pharmaceutical interest as a promising drug target (Costanzi et al, 2012). The invention of endogenous ligands has given birth to the reverse pharmacology approach, which uses orphan GPCRs as a target to identify their ligands This technique is magnificently used for the deorphanization of about 300 GPCRs over two decades (Chung et al, 2007). Human G-protein coupled receptor 87 (hGPR87) plays a crucial role in intracellular signal transduction (Wittenberger et al, 2001) and normal ovarian development as well as ovarian cancer progression. The two most promising reason for targeting this protein are first- GPR87 is the only example of the over expressed GPCRs that can be correlated on a mutation-based level to squamous cell carcinoma of the lung. In the absence of crystal structure, our study provides an early insight into the detailed 3Dstructure of a major drug target or developing new inhibitors for GPR87 which will clearly be a challenging work in the near future
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
