title: Modeling the met form of human tyrosinase: a refined and hydrated pocket for antagonist design.
abstract: Tyrosinases are type 3 copper proteins involved in melanin biosynthesis, responsible for skin and hair color in mammals. To steer tyrosinase inhibitor discovery for therapeutic and cosmetic purposes, structural information about human tyrosinase is necessary. As this protein has never been crystallized so far, we derived a robust homology model built using structural information from Streptomyces castaneoglobisporus and Ipomea batata catecholoxidase enzymes. The active site containing two copper atoms in co-ordination with six histidine residues was refined through an optimization protocol based on molecular mechanics parameters for copper co-ordination and charges calculated by quantum mechanics methods. Five structural water molecules and a hydroxyl ion were found to be essential for optimization. The superimposition of the human homology model on crystallographic structures of tyrosinases from other species revealed similar overall backbone topologies, active site conformations, and conserved water molecules. Phenylthiourea (PTU), the tyrosinase inhibitor of reference, was then docked into the solvated human active pocket. A binding mode consistent with crystallographic information was obtained. Taken together, these findings demonstrated that the human tyrosinase model, deposited in the Protein Model Database, is a reliable structure for future rational inhibitor design projects.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30, Quai Ernest-Ansermet, CH-1211, Geneva, Switzerland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Favre
authors.forename: Antoine
authors.initials: A
authors.lastname: Daina
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D010670:Phenylthiourea / Q000494:pharmacology*; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D004791:Enzyme Inhibitors; D010670:Phenylthiourea; D014442:Monophenol Monooxygenase
keywords: 3-copper proteins; docking; homology modeling; inhibitors; solvation; tyrosinase