Open AccessCrystal structure of cyclophilin A complexed with substrate Ala-Pro suggests a solvent-assisted mechanism of cis-trans isomerization.
Author(s) -
Hengming Ke,
Dale Mayrose,
Wei Cao
Publication year - 1993
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.90.8.3324
Subject(s) - isomerase , chemistry , isomerization , stereochemistry , hydrogen bond , peptidylprolyl isomerase , cyclophilin , active site , peptide bond , cyclophilin a , substrate (aquarium) , prolyl isomerase , crystallography , crystal structure , solvent , molecule , enzyme , catalysis , biochemistry , pin1 , organic chemistry , biology , ecology , microbiology and biotechnology , gene
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.