2ESL

Human Cyclophilin C in Complex with Cyclosporin A

Summary for 2ESL

• Entry DOI: 10.2210/pdb2esl/pdb
• Related: 1BCK 1C5F 1CSA 1CWA 1CWB 1CWC 1CWF 1CWH 1CWI 1CWJ 1CWK 1CWL 1CWM 1CWO 1CYA 1CYB 1CYN 1M63 1MF8 1MIK 1QNG 1QNH 1XQ7 2OJU 2POY 2RMA 2RMB 2RMC 2WFJ 2X2C 2X7K 2Z6W 3BO7 3CYS 3EOV
• Related PRD ID: PRD_000142
• Descriptor: Peptidyl-prolyl cis-trans isomerase C, CYCLOSPORIN A, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: isomerase-immunosuppressant complex, cyclophilin-cyclosporin complex, cyclosporin a, immunosupressant, cyclophilin, sgc, structural genomics, structural genomics consortium, isomerase/immunosuppressant
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm: P45877
• Total number of polymer chains: 12
• Total formula weight: 131405.43

Authors

Walker, J.R.,Davis, T.,Newman, E.M.,Finerty Jr., P.J.,Mackenzie, F.,Weigelt, J.,Sundstrom, M.,Arrowsmith, C.,Edwards, A.,Bochkarev, A.,Dhe-Paganon, S.,Structural Genomics Consortium (SGC) (deposition date: 2005-10-26, release date: 2005-12-13, Last modification date: 2025-03-26)

Primary citation

Davis, T.L.,Walker, J.R.,Campagna-Slater, V.,Finerty, P.J.,Paramanathan, R.,Bernstein, G.,MacKenzie, F.,Tempel, W.,Ouyang, H.,Lee, W.H.,Eisenmesser, E.Z.,Dhe-Paganon, S.
Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases.
PLoS Biol., 8:e1000439-e1000439, 2010

PubMed Abstract: Peptidyl-prolyl isomerases catalyze the conversion between cis and trans isomers of proline. The cyclophilin family of peptidyl-prolyl isomerases is well known for being the target of the immunosuppressive drug cyclosporin, used to combat organ transplant rejection. There is great interest in both the substrate specificity of these enzymes and the design of isoform-selective ligands for them. However, the dearth of available data for individual family members inhibits attempts to design drug specificity; additionally, in order to define physiological functions for the cyclophilins, definitive isoform characterization is required. In the current study, enzymatic activity was assayed for 15 of the 17 human cyclophilin isomerase domains, and binding to the cyclosporin scaffold was tested. In order to rationalize the observed isoform diversity, the high-resolution crystallographic structures of seven cyclophilin domains were determined. These models, combined with seven previously solved cyclophilin isoforms, provide the basis for a family-wide structure:function analysis. Detailed structural analysis of the human cyclophilin isomerase explains why cyclophilin activity against short peptides is correlated with an ability to ligate cyclosporin and why certain isoforms are not competent for either activity. In addition, we find that regions of the isomerase domain outside the proline-binding surface impart isoform specificity for both in vivo substrates and drug design. We hypothesize that there is a well-defined molecular surface corresponding to the substrate-binding S2 position that is a site of diversity in the cyclophilin family. Computational simulations of substrate binding in this region support our observations. Our data indicate that unique isoform determinants exist that may be exploited for development of selective ligands and suggest that the currently available small-molecule and peptide-based ligands for this class of enzyme are insufficient for isoform specificity.

PubMed: 20676357
DOI: 10.1371/journal.pbio.1000439

Experimental method

X-RAY DIFFRACTION (1.9 Å)