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The class A G-protein-coupled receptors (GPCRs) Orexin-1 (OX1) and Orexin-2 (OX2) are located predominantly in the brain and are linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuro-endocrine function, and regulation of the sleep-wake cycle. The natural agonists for OX1 and OX2 are two neuropeptides, Orexin-A and Orexin-B, which have activity at both receptors. Site-directed mutagenesis (SDM) has been reported on both the receptors and the peptides and has provided important insight into key features responsible for agonist activity. However, the structural interpretation of how these data are linked together is still lacking. In this work, we produced and used SDM data, homology modeling followed by MD simulation, and ensemble-flexible docking to generate binding poses of the Orexin peptides in the OX receptors to rationalize the SDM data. We also developed a protein pairwise similarity comparing method (ProS) and a GPCR-likeness assessment score (GLAS) to explore the structural data generated within a molecular dynamics simulation and to help distinguish between different GPCR substates. The results demonstrate how these newly developed methods of structural assessment for GPCRs can be used to provide a working model of neuropeptide-Orexin receptor interaction.

Original publication

DOI

10.1021/bi401119m

Type

Journal article

Journal

Biochemistry

Publication Date

19/11/2013

Volume

52

Pages

8246 - 8260

Keywords

Amino Acid Sequence, Humans, Intracellular Signaling Peptides and Proteins, Models, Chemical, Molecular Docking Simulation, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Neuropeptides, Orexin Receptors, Orexins, Protein Conformation, Receptors, G-Protein-Coupled, Sequence Alignment