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- Title
Modeling the Met Form of Human Tyrosinase: A Refined and Hydrated Pocket for Antagonist Design.
- Authors
Favre, Elisabeth; Daina, Antoine; Carrupt, Pierre ‐ Alain; Nurisso, Alessandra
- 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.
- Subjects
PHENOL oxidase; CHEMICAL inhibitors; COPPER proteins; MELANOGENESIS; MOLECULAR docking; SWEET potato enzymes
- Publication
Chemical Biology & Drug Design, 2014, Vol 84, Issue 2, p206
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12306