1QPF

FK506 BINDING PROTEIN (12 KDA, HUMAN) COMPLEX WITH L-709,858

Summary for 1QPF

• Entry DOI: 10.2210/pdb1qpf/pdb
• Related: 1FKD 1TCO 1YAT 2FKE
• Descriptor: PROTEIN (FK506-BINDING PROTEIN), C32-O-(1-ETHYL-INDOL-5-YL)ASCOMYCIN, heptyl beta-D-glucopyranoside, ... (4 entities in total)
• Functional Keywords: immunophilin-drug complex, cis-trans isomerase, peptidyl-prolyl isomerase, isomerase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytosol : P62942
• Total number of polymer chains: 2
• Total formula weight: 25821.74

Authors

Becker, J.W.,Rotonda, J. (deposition date: 1999-05-24, release date: 1999-08-16, Last modification date: 2023-08-16)

Primary citation

Becker, J.W.,Rotonda, J.,Cryan, J.G.,Martin, M.,Parsons, W.H.,Sinclair, P.J.,Wiederrecht, G.,Wong, F.
32-Indolyl ether derivatives of ascomycin: three-dimensional structures of complexes with FK506-binding protein.
J.Med.Chem., 42:2798-2804, 1999

PubMed Abstract: 32-Indole ether derivatives of tacrolimus and ascomycin retain the potent immunosuppressive activity of their parent compounds but display reduced toxicity. In addition, their complexes with the 12-kDa FK506-binding protein (FKBP) form more stable complexes with the protein phosphatase calcineurin, the molecular target of these drugs. We have solved the three-dimensional structures of the FKBP complexes with two 32-indolyl derivatives of ascomycin. The structures of the protein and the macrolide are remarkably similar to those seen in the complexes with tacrolimus and ascomycin. The indole groups project away from the body of the complex, and multiple conformations are observed for the linkage to these groups as well as for a nearby peptide suggesting apparent flexibility in these parts of the structure. Comparison of these structures with that of the ternary complex of calcineurin, FKBP, and tacrolimus suggests that the indole groups interact with a binding site comprising elements of both the calcineurin alpha- and beta-chains and that this interaction is responsible for the increased stability of these complexes.

PubMed: 10425089
DOI: 10.1021/jm9806042

Experimental method

X-RAY DIFFRACTION (2.5 Å)