Structural insights into the hot spot amino acid residues of mushroom tyrosinase for the bindings of thujaplicins.

Satoshi Takahashi, Takanori Kamiya, Kazunori Saeki, Tomoka Nezu, Shin-Ichiro Takeuchi, Ryoko Takasawa, Satoshi Sunaga, Atsushi Yoshimori, Shigeo Ebizuka, Takehiko Abe, Sei-Ichi Tanuma, Satoshi Takahashi, Takanori Kamiya, Kazunori Saeki, Tomoka Nezu, Shin-ichiro Takeuchi, Ryoko Takasawa, Satoshi Sunaga, Atsushi Yoshimori, Shigeo Ebizuka, Takehiko Abe, Sei-ichi Tanuma

Index: Bioorg. Med. Chem. 18 , 8112-8, (2010)

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Abstract

Tyrosinase inhibitors are important agents for cosmetic products. We examined here the inhibitory effects of three isomers of thujaplicins (α, β and γ) on mushroom tyrosinase and analyzed their binding modes using a homology model from the crystal structure of Streptomyces castaneoglobisporus tyrosinase (PDB ID: 1wx2). All the thujaplicins were found to be competitive inhibitors and γ-thujaplicin has the most potent inhibitory activity (IC(50)=0.07μM). It is noted that there are good correlations between their observed IC(50) values and their binding free energies calculated by MM-GB/SA. The binding modes of thujaplicins were predicted to be similar to that of Tyr98 of caddie protein (ORF378), which was co-crystallized with S. castaneoglobisporus tyrosinase. Furthermore, free energy decomposition analysis indicated that the potent inhibitory activity of γ-thujaplicin is due to the interactions with His242, Val243 and Pro257 (hot spot amino acid residues) at the active site of tyrosinase. These results provide a novel structural insight into the hot spot of mushroom tyrosinase for the specific binding of γ-thujaplicin.Copyright © 2010. Published by Elsevier Ltd.