title: Structural features of the inactive and active states of the melanin-concentrating hormone receptors: insights from molecular simulations.
abstract: Comparative molecular dynamics simulations of both subtypes 1 and 2 of the melanin-concentrating hormone receptor (MCHR1 and MCHR2, respectively) in their free and hormone-bound forms have been carried out. The hormone has been used in its full-length and truncated forms, as well as in 16 mutated forms. Moreover, MCHR1 has been simulated in complex with T-226296, a novel orally active and selective antagonist. The comparative analysis of an extended number of receptor configurations suggests that the differences between inactive (i.e., free and antagonist-bound) and active (i.e., agonist-bound) states of MCHRs involve the receptor portions close to the E/DRY and NPxxY motifs, with prominence to the cytosolic extensions of helices 2, 3, 6, and 7. In fact, the active forms of these receptors share the release of selected intramolecular interactions found in the inactive forms, such as that between R3.50 of the E/DRY motif and D2.40, and that between Y7.53 of the NPxxY motif and F7.60. Another feature of the active forms of both MCHRs is the approach of "helix 8" to the cytosolic extension of helix 3. These features of the active forms are concurrent with the opening of a cleft at the cytosolic end of the helix bundle. For both MCHRs, the agonist-induced chemical information transfer from the extracellular to the cytosolic domains is mediated by a cluster of aromatic amino acids in helix 6, following the ligand interaction with selected amino acids in the extracellular half of the receptor.
authors.affiliation: Department of Chemistry, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Vitale
authors.forename: Carlo
authors.initials: C
authors.lastname: Pedone
authors.forename: Pier G
authors.initials: PG
authors.lastname: De Benedetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Fanelli
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D006860:Hydrogen Bonding; D007028:Hypothalamic Hormones / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008543:Melanins / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D010907:Pituitary Hormones / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000737:chemistry; D012243:Rhodopsin / Q000737:chemistry; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
chemical_list: D001713:Biphenyl Compounds; D007028:Hypothalamic Hormones; D008024:Ligands; C491208:MCHR1 protein, rat; C431280:MCHR2 protein, human; D008543:Melanins; D009281:Naphthalenes; D010446:Peptide Fragments; D010907:Pituitary Hormones; D043562:Receptors, G-Protein-Coupled; D011979:Receptors, Pituitary Hormone; D017481:Receptors, Somatostatin; C457679:T-226296; C092274:melanin-concentrating hormone receptor; C019463:melanin-concentrating hormone; D012243:Rhodopsin