PDBsum entry 1nmk

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Isomerase PDB id
Protein chains
165 a.a. *
SFM ×2
Waters ×208
* Residue conservation analysis
PDB id:
Name: Isomerase
Title: The sanglifehrin-cyclophilin interaction: degradation work, macrocyclic analogues, x-ray crystal structure and binding
Structure: Peptidyl-prolyl cis-trans isomerase a. Chain: a, b. Synonym: ppiase, rotamase, cyclophilin a, cyclosporin a-bin protein. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ppia or cypa. Expressed in: escherichia coli str. K12 substr. W3110. Expression_system_taxid: 316407.
2.10Å     R-factor:   0.165     R-free:   0.189
Authors: J.Kallen,R.Sedrani,J.Wagner
Key ref: R.Sedrani et al. (2003). Sanglifehrin-cyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data. J Am Chem Soc, 125, 3849-3859. PubMed id: 12656618 DOI: 10.1021/ja021327y
10-Jan-03     Release date:   01-Apr-03    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P62937  (PPIA_HUMAN) -  Peptidyl-prolyl cis-trans isomerase A
165 a.a.
165 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Peptidylprolyl isomerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Peptidylproline (omega=180) = peptidylproline (omega=0)
Peptidylproline (omega=180)
= peptidylproline (omega=0)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   8 terms 
  Biological process     viral reproduction   18 terms 
  Biochemical function     protein binding     7 terms  


    Added reference    
DOI no: 10.1021/ja021327y J Am Chem Soc 125:3849-3859 (2003)
PubMed id: 12656618  
Sanglifehrin-cyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data.
R.Sedrani, J.Kallen, L.M.Martin Cabrejas, C.D.Papageorgiou, F.Senia, S.Rohrbach, D.Wagner, B.Thai, A.M.Jutzi Eme, J.France, L.Oberer, G.Rihs, G.Zenke, J.Wagner.
Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC(50) = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C(26)=C(27) exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC(50) = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 A of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20140189 F.P.Davis, and A.Sali (2010).
The overlap of small molecule and protein binding sites within families of protein structures.
  PLoS Comput Biol, 6, e1000668.  
18956864 B.N.Tse, T.M.Snyder, Y.Shen, and D.R.Liu (2008).
Translation of DNA into a library of 13,000 synthetic small-molecule macrocycles suitable for in vitro selection.
  J Am Chem Soc, 130, 15611-15626.  
17391124 H.Hackstein, C.Steinschulte, S.Fiedel, A.Eisele, V.Rathke, T.Stadlbauer, T.Taner, A.W.Thomson, H.Tillmanns, G.Bein, and H.Hölschermann (2007).
Sanglifehrin a blocks key dendritic cell functions in vivo and promotes long-term allograft survival together with low-dose CsA.
  Am J Transplant, 7, 789-798.  
16398698 C.Härtel, P.Iblher, A.Puzik, K.Wortmeier, B.Ebel, C.Schultz, and M.Müller-Steinhardt (2006).
Immunosuppressive activity of the immunophilin-binding drug Sanglifehrin A in human whole blood: potent inhibition of interleukin-6 produced by lymphocytes and monocytes.
  Scand J Immunol, 63, 26-34.  
16302169 X.J.Wang, and F.A.Etzkorn (2006).
Peptidyl-prolyl isomerase inhibitors.
  Biopolymers, 84, 125-146.  
16174436 H.X.Guo, F.Wang, K.Q.Yu, J.Chen, D.L.Bai, K.X.Chen, X.Shen, and H.L.Jiang (2005).
Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/ release.
  Acta Pharmacol Sin, 26, 1201-1211.  
15772070 J.Kallen, R.Sedrani, G.Zenke, and J.Wagner (2005).
Structure of human cyclophilin A in complex with the novel immunosuppressant sanglifehrin A at 1.6 A resolution.
  J Biol Chem, 280, 21965-21971.
PDB code: 1ynd
16134115 T.J.Pemberton, and J.E.Kay (2005).
The cyclophilin repertoire of the fission yeast Schizosaccharomyces pombe.
  Yeast, 22, 927-945.  
  16092970 W.Ou, and J.Silver (2005).
Efficient trapping of HIV-1 envelope protein by hetero-oligomerization with an N-helix chimera.
  Retrovirology, 2, 51.  
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 code is shown on the right.