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PDBsum entry 1m63
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Hydrolase/isomerase/immunosuppressant
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PDB id
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1m63
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Contents |
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372 a.a.
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158 a.a.
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165 a.a.
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11 a.a.
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structure of calcineurin-Cyclophilin-Cyclosporin shows common but distinct recognition of immunophilin-Drug complexes.
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Authors
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Q.Huai,
H.Y.Kim,
Y.Liu,
Y.Zhao,
A.Mondragon,
J.O.Liu,
H.Ke.
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Ref.
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Proc Natl Acad Sci U S A, 2002,
99,
12037-12042.
[DOI no: ]
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PubMed id
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Abstract
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Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, is the common
target for two immunophilin-immunosuppressant complexes, cyclophilin
A-cyclosporin A (CyPA-CsA) and FKBP-FK506. How the two structurally distinct
immunophilin-drug complexes bind the same target has remained unknown. We report
the crystal structure of calcineurin (CN) in complex with CyPA-CsA at 2.8-A
resolution. The CyPA-CsA complex binds to a composite surface formed by the
catalytic and regulatory subunits of CN, where the complex of FK506 and its
binding protein FKBP also binds. While the majority of the CN residues involved
in the binding are common for both immunophilin-immunosuppressant complexes, a
significant number of the residues are distinct. Unlike FKBP-FK506, CyPA-CsA
interacts with Arg-122 at the active site of CN, implying direct involvement of
CyPA-CsA in the regulation of CN catalysis. The simultaneous interaction of CyPA
with both the composite surface and the active site of CN suggests that the
composite surface may serve as a substrate recognition site responsible for the
narrow substrate specificity of CN. The comparison of CyPA-CsA-CN with
FKBP-FK506-CN significantly contributes to understanding the molecular basis of
regulation of CN activity by the immunophilin-immunosuppressant.
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Figure 2.
Fig 2. Ribbon representation of CyPA-CsA-CN. Color codes
are CNA, gold; CNB, cyan; CsA, green; CyPA, red; Zn2+ and Fe^3+,
pink; and calcium, blue. The residues from CN involved in
binding of CyPA-CsA are shown as blue balls.
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Figure 4.
Fig 4. Interfacial interactions between CN and
immunophilins-immunosuppressants. CNA and CNB are shown as
yellow and cyan ribbons. (A) The CN composite surface for
CyPA-CsA binding. A total of 25 residues of CN are involved in
interaction with CyPA-CsA: Arg-122, Tyr-159, Phe-160, Leu-312,
Val-314, Tyr-315, Tyr-341, Trp-342, Pro-344, Asn-345, Trp-352,
Ser-353, Pro-355, Phe-356, and Glu-359 of CNA, and Glu-47,
Gln-50, Met-118, Val-119, Asn-122, Leu-123, Lys-124, and Lys-164
of CNB. Red balls represent residues interacting with CyPA and
green balls represent residues interacting with CsA (green
sticks). The residues from CNB are marked with the letter "B"
attached to the residue number. (B) The CN surface for binding
of CyPA-CsA and FKBP12-FK506. CN residues in red interact with
both CyPA-CsA and FKBP12-FK506. Green residues are unique for
CyPA-CsA binding and blue residues are unique for FKBP-FK506.
CsA and FK506 are shown as green and blue sticks. (C) CyPA
residues for recognition of CN (gold) and CsA (blue). CsA is
shown in green sticks.
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