Specificity of trypsin and chymotrypsin: Loop-motion-controlled dynamic correlation as a determinant

被引:116
作者
Ma, WZ
Tang, C
Lai, LH [1 ]
机构
[1] Peking Univ, Ctr Theoret Biol, Beijing 100871, Peoples R China
[2] Peking Univ, Coll Chem, State Key Lab Struct Chem Stable & Unstable Speci, Beijing 100871, Peoples R China
[3] Univ Calif San Francisco, Calif Inst Quantitat Biomed Res, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Calif Inst Quantitat Biomed Res, Dept Biochem, San Francisco, CA 94143 USA
[5] Univ Calif San Francisco, Calif Inst Quantitat Biomed Res, Dept Biophys, San Francisco, CA 94143 USA
基金
美国国家科学基金会; 中国国家自然科学基金;
关键词
D O I
10.1529/biophysj.104.057158
中图分类号
Q6 [生物物理学];
学科分类号
071011 ;
摘要
Trypsin and chymotrypsin are both serine proteases with high sequence and structural similarities, but with different substrate specificity. Previous experiments have demonstrated the critical role of the two loops outside the binding pocket in controlling the specificity of the two enzymes. To understand the mechanism of such a control of specificity by distant loops, we have used the Gaussian network model to study the dynamic properties of trypsin and chymotrypsin and the roles played by the two loops. A clustering method was introduced to analyze the correlated motions of residues. We have found that trypsin and chymotrypsin have distinct dynamic signatures in the two loop regions, which are in turn highly correlated with motions of certain residues in the binding pockets. Interestingly, replacing the two loops of trypsin with those of chymotrypsin changes the motion style of trypsin to chymotrypsin- like, whereas the same experimental replacement was shown necessary to make trypsin have chymotrypsin's enzyme specificity and activity. These results suggest that the cooperative motions of the two loops and the substrate- binding sites contribute to the activity and substrate specificity of trypsin and chymotrypsin.
引用
收藏
页码:1183 / 1193
页数:11
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