Structural insights into the hot spot amino acid residues of mushroom tyrosinase for the bindings of thujaplicins.
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.
Institute for Theoretical Medicine, Inc., 4259-3 Nagatsuda-cho, Midori-ku, Yokohama 226-8510, Japan.
Satoshi
S
Takahashi
Takanori
T
Kamiya
Kazunori
K
Saeki
Tomoka
T
Nezu
Shin-Ichiro
S
Takeuchi
Ryoko
R
Takasawa
Satoshi
S
Sunaga
Atsushi
A
Yoshimori
Shigeo
S
Ebizuka
Takehiko
T
Abe
Sei-Ichi
S
Tanuma
D000363:Agaricales / Q000201:enzymology*; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D001667:Binding, Competitive; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D007536:Isomerism; D007700:Kinetics; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000737:chemistry* / Q000378:metabolism; D039821:Monoterpenes / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D016415:Sequence Alignment; D013302:Streptomyces / Q000201:enzymology; D014334:Tropolone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
C116333:2-hydroxy-5-isopropyl- 2,4,6-cycloheptatrienone; D000596:Amino Acids; D001426:Bacterial Proteins; D039821:Monoterpenes; C556010:alpha-thujaplicin; D014334:Tropolone; D014442:Monophenol Monooxygenase; C009479:beta-thujaplicin