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

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• 作者：Satoshi Takahashi ; Takanori Kamiya ; Kazunori Saeki ; Tomoka Nezu ; Shin-ichiro Takeuchi ; Ryoko Takasawa ; Satoshi Sunaga ; Atsushi Yoshimori ; Shigeo Ebizuka ; Takehiko Abe ; Sei-ichi Tanuma
• 关键词：Tyrosinase ; Thujaplicins ; Hot spot ; Homology modeling ; MM-GB/SA ; Free energy decomposition analysis
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2010
• 出版时间：15 November 2010
• 年：2010
• 卷：18
• 期：22
• 页码：8112-8118
• 全文大小：1098 K

文摘

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 (IC₅₀ = 0.07 μM). It is noted that there are good correlations between their observed IC₅₀ 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.