Ke H, Mayrose D, Cao W
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill 27599.
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3324-8. doi: 10.1073/pnas.90.8.3324.
Cyclophilin is a binding protein for the immunosuppressive drug cyclosporin A and is also an enzyme with peptidyl-prolyl cis-trans isomerase activity. The crystal structure of cyclophilin A complexed with the substrate Ala-Pro has been determined and refined to an R factor of 0.196 at 1.64-A resolution. The structure shows that only the cis form of Ala-Pro binds cyclophilin A despite the fact that Ala-Pro has an equilibrium majority of the trans form in solution. Simulation of the cis-trans isomerization in an ESV10 graphics system suggests a solvent-assisted mechanism in which first the peptidyl-prolyl bond is desolvated at the ground state by binding to the hydrophobic pocket of the active site, and later the intermediate state is stabilized by a hydrogen bond between the carbonyl oxygen of the amide bond and a bound water molecule.
亲环蛋白是免疫抑制药物环孢菌素A的结合蛋白，也是一种具有肽基脯氨酰顺反异构酶活性的酶。已确定并精制了与底物丙氨酰-脯氨酸复合的亲环蛋白A的晶体结构，在1.64埃分辨率下R因子为0.196。该结构表明，尽管丙氨酰-脯氨酸在溶液中以反式为主，但只有顺式的丙氨酰-脯氨酸能结合亲环蛋白A。在ESV10图形系统中对顺反异构化的模拟表明，这是一种溶剂辅助机制，其中首先肽基脯氨酰键在基态通过与活性位点的疏水口袋结合而脱溶剂化，随后中间态通过酰胺键的羰基氧与结合的水分子之间的氢键得以稳定。
