Structural insights into human GPCR protein OA1 a

Authors: Anirban Ghosh Uddhavesh Sonavane Sai Krishna Andhirka Gopala Krishna Aradhyam Rajendra Joshi

Publish Date: 2011/09/22

Volume: 18, Issue: 5, Pages: 2117-2133

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Abstract

Human ocular albinism type 1 protein OA1—a member of the Gprotein coupled receptor GPCR superfamily—is an integral membrane glycoprotein expressed exclusively by intracellular organelles known as melanocytes and is responsible for the proper biogenesis of melanosomes Mutations in the Oa1 gene are responsible for the disease ocular albinism Despite its clinical importance there is a lack of indepth understanding of its structure and mechanism of activation due to the absence of a crystal structure In the present study homology modeling was applied to predicting OA1 structure following thorough sequence analysis and secondary structure predictions The predicted model had the signature residues and motifs expected of GPCRs and was used for carrying out molecular docking studies with an endogenous ligand lDOPA and an antagonist dopamine the results agreed quite well with the available experimental data Finally three sets of explicit molecular dynamics simulations were carried out in lipid bilayer the results of which not only confirmed the stability of the predicted model but also helped witness some differences in structural features such as rotamer toggle switch helical tilts and hydrogen bonding pattern that helped distinguish between the agonist and antagonistbound receptor forms In place of the typical “D/ERY”motifmediated “ionic lock” a hydrogen bond mediated by the “DAY” motif was observed that could be used to distinguish the agonist and antagonist bound forms of OA1 In the absence of a crystal structure this study helped to shed some light on the structural features of OA1 and its behavior in the presence of an agonist and an antagonist which might be helpful in the future drug discovery process for ocular albinismAG UBS and RRJ gratefully acknowledge the Department of Information Technology DIT Government of India New Delhi for providing financial support This work was performed using the “Bioinformatics Resources and Applications Facility BRAF” at CDAC Pune funded by DIT New Delhi AGK and ASK gratefully acknowledge funding support from IIT Madras Department of Science and Technology DST and Department of Biotechnology DBT Government of India

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