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PDBsum entry 1mf8

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Hydrolase/isomerase/immunosuppressant PDB id
1mf8
Jmol
Contents
Protein chains
352 a.a. *
164 a.a. *
164 a.a. *
11 a.a. *
Ligands
PO4
Metals
_CA ×4
* Residue conservation analysis

References listed in PDB file
Key reference
Title Crystal structure of human calcineurin complexed with cyclosporin a and human cyclophilin.
Authors L.Jin, S.C.Harrison.
Ref. Proc Natl Acad Sci U S A, 2002, 99, 13522-13526. [DOI no: 10.1073/pnas.212504399]
PubMed id 12357034
Abstract
Calcineurin (Cn), a Ca(2+)/calmodulin-dependent Ser/Thr protein phosphatase, is an important participant in signaling pathways that activate T cells. It is the target of the immunosuppressive drugs cyclosporin A (CsA) and FK506. These drugs bind proteins known as cyclophilin (Cyp) and FK506-binding protein, respectively, and the drug-protein complexes in turn inhibit Cn. We report the crystal structure of a Cyp/CsA/Cn ternary complex, determined to a resolution of 3.1 A. Residues 3-9 of CsA, particularly N-methyl leucines 4 and 6, and Trp-121 of Cyp form a composite surface for interaction with Cn. The hydrophobic interface buries two hydrogen bonds. The structure accounts clearly for the effects of mutations in Cn on CsA-resistance and for the way modifications of CsA alter immunosuppressive activity.
Figure 1.
Fig 1. Ribbon diagrams of the Cyp/CsA/Cn ternary complex (A), and the FKBP/FK506/Cn complex (B) (2, 3). CsA and FK506 are shown in ball-and-stick representations; CnA is in yellow (with the CnB-binding segment in dark yellow); CnB, red; Cyp, green; FKBP, blue; and Ca^2+ ions, cyan balls. The Cn active-site cleft is indicated with an asterisk.
Figure 3.
Fig 3. Details of the interaction between CsA and Cn. CsA, ball-and-stick; CnA, yellow; CnB, red; Cyp, green. Some Cn and Cyp residues involved in CsA binding are represented as ball-and-sticks. The backbone positions of other residues mentioned in the text (CnA344Pro, CnA353Ser, CnB118Met, CnB122Asn, Cyp103Ala) are shown as gray spheres. There are two hydrophobic surfaces for CsA binding, one formed by residues from CnA and CnB (upper right) and the other formed jointly by CnA and Cyp (lower left). The two hydrogen bonds between CsA and CnA are indicated as broken lines.
PROCHECK
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