title: Structural insights into human GPCR protein OA1: a computational perspective.
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.
authors.affiliation: Centre for Development of Advanced Computing (C-DAC), Pune University Campus, Pune, India.
authors.forename: Anirban
authors.initials: A
authors.lastname: Ghosh
authors.forename: Uddhavesh
authors.initials: U
authors.lastname: Sonavane
authors.forename: Sai Krishna
authors.initials: SK
authors.lastname: Andhirka
authors.forename: Gopala Krishna
authors.initials: GK
authors.lastname: Aradhyam
authors.forename: Rajendra
authors.initials: R
authors.lastname: Joshi
mesh_terms: D000595:Amino Acid Sequence; D030562:Databases, Protein; D004298:Dopamine / Q000737:chemistry*; D005136:Eye Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D007980:Levodopa / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011789:Quantum Theory; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D005136:Eye Proteins; C095276:GPR143 protein, human; D008051:Lipid Bilayers; D008562:Membrane Glycoproteins; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D007980:Levodopa; D004298:Dopamine