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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
PDB id:
1mf8
Name: Hydrolase/isomerase/immunosuppressant
Title: Crystal structure of human calcineurin complexed with cyclos and human cyclophilin
Structure: Calmodulin-dependent calcineurin a subunit, alpha chain: a. Fragment: truncated form (residues 20-392). Synonym: serine/threonine protein phosphatase 2b catalytic alpha isoform, cam-prp catalytic subunit. Engineered: yes. Calcineurin b subunit isoform 1. Chain: b. Synonym: protein phosphatase 2b regulatory subunit 1, prote
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Tolypocladium inflatum. Organism_taxid: 29910
Biol. unit: Tetramer (from PQS)
Resolution:
3.10Å     R-factor:   0.250     R-free:   0.300
Authors: L.Jin,S.C.Harrison
Key ref:
L.Jin and S.C.Harrison (2002). Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin. Proc Natl Acad Sci U S A, 99, 13522-13526. PubMed id: 12357034 DOI: 10.1073/pnas.212504399
Date:
09-Aug-02     Release date:   16-Oct-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q08209  (PP2BA_HUMAN) -  Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform
Seq:
Struc: 		 
Seq:
Struc: 		521 a.a.
352 a.a.
Protein chain
Pfam   ArchSchema ?
P63098  (CANB1_HUMAN) -  Calcineurin subunit B type 1
Seq:
Struc: 		170 a.a.
164 a.a.
Protein chain
Pfam   ArchSchema ?
P62937  (PPIA_HUMAN) -  Peptidyl-prolyl cis-trans isomerase A
Seq:
Struc: 		165 a.a.
164 a.a.
Protein chain
No UniProt id for this chain
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: Chain A: E.C.3.1.3.16  - Phosphoprotein phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: A phosphoprotein + H2O = a protein + phosphate
phosphoprotein
 + H(2)O
 = protein
 +
phosphate
Bound ligand (Het Group name = PO4)
corresponds exactly
   Enzyme class 3: Chain C: E.C.5.2.1.8  - Peptidylprolyl isomerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Peptidylproline (omega=180) = peptidylproline (omega=0)
Peptidylproline (omega=180)
 = 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
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   5 terms 
  Biological process     viral reproduction   24 terms 
  Biochemical function     hydrolase activity     11 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.212504399 Proc Natl Acad Sci U S A 99:13522-13526 (2002)
PubMed id: 12357034  
 
 
Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin.
L.Jin, S.C.Harrison.
 
  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.
 
  Selected figure(s)  
 
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.
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21245533 A.Kuglstatter, F.Mueller, E.Kusznir, B.Gsell, M.Stihle, R.Thoma, J.Benz, L.Aspeslet, D.Freitag, and M.Hennig (2011).
Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin).
  Acta Crystallogr D Biol Crystallogr, 67, 119-123.
PDB codes: 3odi 3odl
21115349 H.Li, A.Rao, and P.G.Hogan (2011).
Interaction of calcineurin with substrates and targeting proteins.
  Trends Cell Biol, 21, 91.  
21472561 P.D.Dearmond, G.M.West, H.T.Huang, and M.C.Fitzgerald (2011).
Stable isotope labeling strategy for protein-ligand binding analysis in multi-component protein mixtures.
  J Am Soc Mass Spectrom, 22, 418-430.  
21288162 S.R.Pereira, V.T.Vasconcelos, and A.Antunes (2011).
The phosphoprotein phosphatase family of Ser/Thr phosphatases as principal targets of naturally occurring toxins.
  Crit Rev Toxicol, 41, 83.  
20602248 A.Galat, and J.Bua (2010).
Molecular aspects of cyclophilins mediating therapeutic actions of their ligands.
  Cell Mol Life Sci, 67, 3467-3488.  
20552635 Q.Chen, W.Wu, J.Li, and Q.Wei (2010).
The polarity of the amino acid residue 118 of calcineurin B is closely linked to calcineurin enzyme activity.
  IUBMB Life, 62, 561-567.  
19832699 S.Malouitre, H.Dube, D.Selwood, and M.Crompton (2010).
Mitochondrial targeting of cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation.
  Biochem J, 425, 137-148.  
19285944 A.Rodríguez, J.Roy, S.Martínez-Martínez, M.D.López-Maderuelo, P.Niño-Moreno, L.Ortí, D.Pantoja-Uceda, A.Pineda-Lucena, M.S.Cyert, and J.M.Redondo (2009).
A conserved docking surface on calcineurin mediates interaction with substrates and immunosuppressants.
  Mol Cell, 33, 616-626.  
19770360 J.Brewin, C.Mancao, K.Straathof, H.Karlsson, S.Samarasinghe, P.J.Amrolia, and M.Pule (2009).
Generation of EBV-specific cytotoxic T cells that are resistant to calcineurin inhibitors for the treatment of posttransplantation lymphoproliferative disease.
  Blood, 114, 4792-4803.  
19290928 J.O.Liu (2009).
Calmodulin-dependent phosphatase, kinases, and transcriptional corepressors involved in T-cell activation.
  Immunol Rev, 228, 184-198.  
19860902 M.Sieber, and R.Baumgrass (2009).
Novel inhibitors of the calcineurin/NFATc hub - alternatives to CsA and FK506?
  Cell Commun Signal, 7, 25.  
19855826 W.C.Van Voorhis, W.G.Hol, P.J.Myler, and L.J.Stewart (2009).
The role of medical structural genomics in discovering new drugs for infectious diseases.
  PLoS Comput Biol, 5, e1000530.  
19879837 Y.Shi (2009).
Serine/threonine phosphatases: mechanism through structure.
  Cell, 139, 468-484.  
19734911 Y.Zhang, F.Erdmann, and G.Fischer (2009).
Augmented photoswitching modulates immune signaling.
  Nat Chem Biol, 5, 724-726.  
18488168 B.Wang, P.Zhang, and Q.Wei (2008).
Recent progress on the structure of Ser/Thr protein phosphatases.
  Sci China C Life Sci, 51, 487-494.  
18384083 Q.Ye, H.Wang, J.Zheng, Q.Wei, and Z.Jia (2008).
The complex structure of calmodulin bound to a calcineurin peptide.
  Proteins, 73, 19-27.
PDB code: 2r28
18212100 R.G.Ptak, P.A.Gallay, D.Jochmans, A.P.Halestrap, U.T.Ruegg, L.A.Pallansch, M.D.Bobardt, M.P.de Béthune, J.Neyts, E.De Clercq, J.M.Dumont, P.Scalfaro, K.Besseghir, R.M.Wenger, and B.Rosenwirth (2008).
Inhibition of human immunodeficiency virus type 1 replication in human cells by Debio-025, a novel cyclophilin binding agent.
  Antimicrob Agents Chemother, 52, 1302-1317.  
17502104 K.Takeuchi, M.H.Roehrl, Z.Y.Sun, and G.Wagner (2007).
Structure of the calcineurin-NFAT complex: defining a T cell activation switch using solution NMR and crystal coordinates.
  Structure, 15, 587-597.
PDB code: 2jog
17499048 M.J.Sánchez-Barrena, H.Fujii, I.Angulo, M.Martínez-Ripoll, J.K.Zhu, and A.Albert (2007).
The structure of the C-terminal domain of the protein kinase AtSOS2 bound to the calcium sensor AtSOS3.
  Mol Cell, 26, 427-435.
PDB code: 2ehb
17694572 M.Sieber, M.Karanik, C.Brandt, C.Blex, M.Podtschaske, F.Erdmann, R.Rost, E.Serfling, J.Liebscher, M.Pätzel, A.Radbruch, G.Fischer, and R.Baumgrass (2007).
Inhibition of calcineurin-NFAT signaling by the pyrazolopyrimidine compound NCI3.
  Eur J Immunol, 37, 2617-2626.  
  17277440 V.Venugopal, B.Sen, A.K.Datta, and R.Banerjee (2007).
Structure of cyclophilin from Leishmania donovani at 1.97 A resolution.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 60-64.
PDB code: 2haq
17505522 W.J.Steinbach, J.L.Reedy, R.A.Cramer, J.R.Perfect, and J.Heitman (2007).
Harnessing calcineurin as a novel anti-infective agent against invasive fungal infections.
  Nat Rev Microbiol, 5, 418-430.  
16505102 C.Marchand, S.Antony, K.W.Kohn, M.Cushman, A.Ioanoviciu, B.L.Staker, A.B.Burgin, L.Stewart, and Y.Pommier (2006).
A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex.
  Mol Cancer Ther, 5, 287-295.  
16903851 D.J.Loane, G.A.Hicks, B.A.Perrino, and N.V.Marrion (2006).
Inhibition of BK channel activity by association with calcineurin in rat brain.
  Eur J Neurosci, 24, 433-441.  
16913847 D.Y.Yu, J.Luo, F.Bu, G.J.Song, L.Q.Zhang, and Q.Wei (2006).
Inhibition of calcineurin by infusion of CsA causes hyperphosphorylation of tau and is accompanied by abnormal behavior in mice.
  Biol Chem, 387, 977-983.  
16885030 N.Leulliot, G.Vicentini, J.Jordens, S.Quevillon-Cheruel, M.Schiltz, D.Barford, H.van Tilbeurgh, and J.Goris (2006).
Crystal structure of the PP2A phosphatase activator: implications for its PP2A-specific PPIase activity.
  Mol Cell, 23, 413-424.
PDB codes: 2ixm 2ixn 2ixo 2ixp
15845546 B.Adams, A.Musiyenko, R.Kumar, and S.Barik (2005).
A novel class of dual-family immunophilins.
  J Biol Chem, 280, 24308-24314.  
16131541 B.Chan, G.Greenan, F.McKeon, and T.Ellenberger (2005).
Identification of a peptide fragment of DSCR1 that competitively inhibits calcineurin activity in vitro and in vivo.
  Proc Natl Acad Sci U S A, 102, 13075-13080.  
16113294 J.R.Blankenship, and J.Heitman (2005).
Calcineurin is required for Candida albicans to survive calcium stress in serum.
  Infect Immun, 73, 5767-5774.  
15998457 P.Wang, and J.Heitman (2005).
The cyclophilins.
  Genome Biol, 6, 226.  
15749159 Y.Pommier, and J.Cherfils (2005).
Interfacial inhibition of macromolecular interactions: nature's paradigm for drug discovery.
  Trends Pharmacol Sci, 26, 138-145.  
15230980 R.Kumar, A.Musiyenko, A.Oldenburg, B.Adams, and S.Barik (2004).
Post-translational generation of constitutively active cores from larger phosphatases in the malaria parasite, Plasmodium falciparum: implications for proteomics.
  BMC Mol Biol, 5, 6.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.