PDBsum entry 1m63

Hydrolase/isomerase/immunosuppressant

PDB id: 1m63

Contents

Protein chains

372 a.a. *

158 a.a. *

165 a.a. *

11 a.a. *

Metals

_FE ×2

_CA ×8

_ZN ×2

* Residue conservation analysis

PDB id:

1m63

Name:

Hydrolase/isomerase/immunosuppressant

Title:

Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes

Structure:

Serine/threonine protein phosphatase 2b catalytic subunit, alpha isoform. Chain: a, e. Fragment: residues 1-372. Synonym: calmodulin-dependent calineurin a subunit, alpha isoform, cam-prp subunit. Engineered: yes. Calcineurin b subunit isoform 1. Chain: b, f.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cna alpha. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Gene: cnb. Synthetic: yes. Tolypocladium inflatum.

Biol. unit:

Pentamer (from PQS)

Resolution:

2.80Å R-factor: 0.260 R-free: 0.322

Authors:

Q.Huai,H.-Y.Kim,Y.Liu,Y.Zhao,A.Mondragon,J.O.Liu,H.Ke

Key ref:

Q.Huai et al. (2002). Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes. Proc Natl Acad Sci U S A, 99, 12037-12042. PubMed id: 12218175 DOI: 10.1073/pnas.192206699

Date:

12-Jul-02 Release date: 25-Sep-02

Protein chains

Q08209  (PP2BA_HUMAN) -  Protein phosphatase 3 catalytic subunit alpha from Homo sapiens

Seq: 521 a.a.

Struc: 372 a.a.

Protein chains

P63098  (CANB1_HUMAN) -  Calcineurin subunit B type 1 from Homo sapiens

Seq: 170 a.a.

Struc: 158 a.a.

Protein chains

P62937  (PPIA_HUMAN) -  Peptidyl-prolyl cis-trans isomerase A from Homo sapiens

Seq: 165 a.a.

Struc: 165 a.a.

Protein chains

No UniProt id for this chain

Struc: 11 a.a.

Enzyme reactions

• Enzyme class 2: Chains A, E: E.C.3.1.3.16 - protein-serine/threonine phosphatase.
• Reaction:
  1. O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate
  2. O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate
• Enzyme class 3: Chains C, G: E.C.5.2.1.8 - peptidylprolyl isomerase.
• Reaction: [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1073/pnas.192206699

Proc Natl Acad Sci U S A 99:12037-12042 (2002)

PubMed id: 12218175

Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes.

Q.Huai, H.Y.Kim, Y.Liu, Y.Zhao, A.Mondragon, J.O.Liu, H.Ke.

ABSTRACT

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.

Selected figure(s)

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.

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.

Figures were selected by the author.