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Journal of Molecular Modeling

, Volume 18, Issue 5, pp 2117–2133 | Cite as

Structural insights into human GPCR protein OA1: a computational perspective

  • Anirban Ghosh
  • Uddhavesh Sonavane
  • Sai Krishna Andhirka
  • Gopala Krishna Aradhyam
  • Rajendra Joshi
Original Paper

Abstract

Human ocular albinism type 1 protein (OA1)—a member of the G-protein 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 in-depth 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, l-DOPA 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 antagonist-bound receptor forms. In place of the typical “D/ERY”-motif-mediated “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 albinism.

Keywords

G-protein coupled receptor Ocular albinism l-DOPA Dopamine Homology modeling Molecular docking Molecular dynamics simulation 

Notes

Acknowledgments

A.G., U.B.S. and R.R.J. 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 C-DAC, Pune, funded by DIT, New Delhi. A.G.K. and A.S.K. gratefully acknowledge funding support from IIT Madras, Department of Science and Technology (DST) and Department of Biotechnology (DBT), Government of India.

Supplementary material

894_2011_1228_MOESM1_ESM.pdf (235 kb)
Supplementary Fig. 1 (PDF 235 kb)
894_2011_1228_MOESM2_ESM.pdf (267 kb)
Supplementary Fig. 2 (PDF 267 kb)
894_2011_1228_MOESM3_ESM.pdf (104 kb)
Supplementary Fig. 3 (PDF 103 kb)
894_2011_1228_MOESM4_ESM.pdf (252 kb)
Supplementary Fig. 4 (PDF 252 kb)
894_2011_1228_MOESM5_ESM.pdf (116 kb)
Supplementary Table 1 (PDF 115 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Anirban Ghosh
    • 1
  • Uddhavesh Sonavane
    • 1
  • Sai Krishna Andhirka
    • 2
  • Gopala Krishna Aradhyam
    • 2
  • Rajendra Joshi
    • 1
  1. 1.Bioinformatics GroupCentre for Development of Advanced Computing (C-DAC)PuneIndia
  2. 2.Department of BiotechnologyIndian Institute of Technology MadrasChennaiIndia

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