1CWB

THE X-RAY STRUCTURE OF (MEBM2T)1-CYCLOSPORIN COMPLEXED WITH CYCLOPHILIN A PROVIDES AN EXPLANATION FOR ITS ANOMALOUSLY HIGH IMMUNOSUPPRESSIVE ACTIVITY

Summary for 1CWB

• Entry DOI: 10.2210/pdb1cwb/pdb
• Related: 1BCK 1C5F 1CSA 1CWA 1CWC 1CWF 1CWH 1CWI 1CWJ 1CWK 1CWL 1CWM 1CWO 1CYA 1CYB 1CYN 1IKF 1M63 1MF8 1MIK 1QNG 1QNH 1XQ7 2ESL 2OJU 2POY 2RMA 2RMB 2RMC 2WFJ 2X2C 2X7K 2Z6W 3BO7 3CYS 3EOV
• Related PRD ID: PRD_000765
• Descriptor: PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A, CYCLOSPORIN A (3 entities in total)
• Functional Keywords: isomerase-immunosuppressant complex, cyclophilin-cyclosporin complex, cyclosporin a, immunosuppressant, cyclophilin, isomerase/immunosuppressant
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 19271.16

Authors

Mikol, V.,Kallen, J.,Walkinshaw, M.D. (deposition date: 1995-09-06, release date: 1996-01-29, Last modification date: 2024-06-05)

Primary citation

Mikol, V.,Kallen, J.,Walkinshaw, M.D.
The X-Ray Structure of (Mebm2T)1-Cyclosporin Complexed with Cyclophilin a Provides an Explanation for its Anomalously High Immunosuppressive Activity.
Protein Eng., 7:597-, 1994

PubMed Abstract: For most of the cyclosporin A (CsA) analogs, there is generally a good correlation between cyclophilin binding and immunosuppression. However, this relationship does not seem to hold for 4-[(E)-2-butenyl]-4,4,N-trimethyl-L-threonine1 (MeBm2t)1-CsA. Its affinity for cyclophilin was reported to be approximately 1% that of CsA and its immunosuppressive activity in vitro was shown to be approximately 30% that of CsA. We report here the crystal structure of a complex between recombinant human cyclophilin A (CypA) and (MeBm2t)1-CsA which has been determined by X-ray crystallography at 2.2 A resolution and refined to an R-factor of 16.3%. (MeBm2t)1-CsA shows a similar bound conformation and network of interactions to CypA as CsA. The measured lower affinity for CypA cannot therefore be explained by a different mode of binding. We propose that the poor affinity to CypA could be accounted for by the existence of an equilibrium in aqueous solution between a 'cyclophilin bound conformation' and a 'non-binding conformation' of (MeBm2t)1-CsA. The relatively high immunosuppressive activity is suggested to result from slight conformational differences observed in the effector domain.

PubMed: 8073029
DOI: 10.1093/PROTEIN/7.5.597

Experimental method

X-RAY DIFFRACTION (2.2 Å)