Mechanistic Implication of Crystal Structures of the Cyclophilin−Dipeptide Complexes

• Published in: Biochemistry (Easton) Vol. 35; no. 23; pp. 7362 - 7368
• Main Authors: Zhao, Yingdong, Ke, Hengming
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11.06.1996
• Subjects: Amino Acid Isomerases - chemistry; Amino Acid Isomerases - metabolism; Amino Acid Sequence; Binding Sites; Binding, Competitive; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Computer Graphics; Cyclosporins - metabolism; Dipeptides - chemistry; Dipeptides - metabolism; Humans; Hydrogen Bonding; Models, Molecular; Models, Structural; Peptidylprolyl Isomerase; Protein Conformation; Protein Structure, Secondary; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Software; Substrate Specificity
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi960278x

The structures of cyclophilin A complexed with dipeptides of Ser-Pro, His-Pro, and Gly-Pro have been determined and refined at high resolution. Comparison of these structures revealed that the dipeptide complexes have the same molecular conformation and the same binding of the dipeptides. The side chains of the N-terminal amino acid of the above dipeptides do not strongly interact with cyclophilin, implying their minor contribution to the cis − trans isomerization and thus accounting for the broad catalytic specificity of the enzyme. The binding of the dipeptides is similar to that of the common substrate succinyl-Ala-Ala-Pro-Phe-p-nitroanilide in terms of the N-terminal hydrogen bonding and the hydrophobic interaction of the proline side chain. However, substantial differences between these structures are observed in (1) hydrogen bonding between the carboxyl terminus of the peptides and Arg55 and between Arg55 and Gln63, (2) the side chain conformation of Arg55, and (3) water binding at the active site. These differences imply either that dipeptides are not substrates but competitive inhibitors of peptidyl-prolyl cis − trans isomerases or that dipeptides are subject to different catalytic mechanisms from tetrapeptides.