title: Crystal structure of cyclophilin A complexed with substrate Ala-Pro suggests a solvent-assisted mechanism of cis-trans isomerization.
abstract: 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.
authors: Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill 27599.
authors: H
authors: H
authors: Ke
authors: D
authors: D
authors: Mayrose
authors: W
authors: W
authors: Cao
mesh_terms: D000591:Amino Acid Isomerases / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D016572:Cyclosporine / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism*; D007536:Isomerism; D008958:Models, Molecular; D019696:Peptidylprolyl Isomerase; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012997:Solvents; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D002352:Carrier Proteins; D004151:Dipeptides; D012997:Solvents; C038123:alanylproline; D016572:Cyclosporine; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase