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Science 8 October 1993:
Vol. 262. no. 5131, pp. 248 - 250
DOI: 10.1126/science.8211144
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Articles

Science, Vol 262, Issue 5131, 248-250
Copyright © 1993 by American Association for the Advancement of Science

articles

Structure-based design of a cyclophilin-calcineurin bridging ligand

DG Alberg and SL Schreiber

Department of Chemistry, Harvard University, Cambridge, MA 02138.

The affinity of a flexible ligand that adopts a specific conformation when bound to its receptor should be increased with the appropriate use of conformational restraints. By determining the structure of protein-ligand complexes, such restraints can in principle be designed into the bound ligand in a rational way. A tricyclic variant (TCsA) of the immunosuppressant cyclosporin A (CsA), which inhibits the proliferation of T lymphocytes by forming a cyclophilin-CsA-calcineurin complex, was designed with the known three-dimensional structure of a cyclophilin-CsA complex. The conformational restraints in TCsA appear to be responsible for its greater affinity for cyclophilin and calcineurin relative to CsA.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin.
L. Jin and S. C. Harrison (2002)
PNAS 99, 13522-13526
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Selective disruption of protein aggregation by cyclodextrin dimers.
D. K. Leung, Z. Yang, and R. Breslow (2000)
PNAS 97, 5050-5053
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