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PDBsum entry 1cyb
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Immunosuppressant PDB id
1cyb

 

 

 

 

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Contents
Protein chain
11 a.a.
PDB id:
1cyb
Name: Immunosuppressant
Title: Nmr studies of (u-13c)cyclosporin a bound to cyclophilin: bound conformation and portions of cyclosporin involved in binding
Structure: Cyclosporin a. Chain: a. Synonym: cyclosporine, ciclosporin, ciclosporine. Engineered: yes
Source: Synthetic: yes. Tolypocladium inflatum. Organism_taxid: 29910
NMR struc: 20 models
Authors: S.W.Fesik
Key ref:
S.W.Fesik et al. (1991). NMR studies of [U-13C]cyclosporin A bound to cyclophilin: bound conformation and portions of cyclosporin involved in binding. Biochemistry, 30, 6574-6583. PubMed id: 2054356 DOI: 10.1021/bi00240a030
Date:
24-Feb-92     Release date:   31-Jan-94    
PROCHECK
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 Headers
 References

Protein chain
No UniProt id for this chain
Struc: 11 a.a.
Key:    Secondary structure

 

 
DOI no: 10.1021/bi00240a030 Biochemistry 30:6574-6583 (1991)
PubMed id: 2054356  
 
 
NMR studies of [U-13C]cyclosporin A bound to cyclophilin: bound conformation and portions of cyclosporin involved in binding.
S.W.Fesik, R.T.Gampe, H.L.Eaton, G.Gemmecker, E.T.Olejniczak, P.Neri, T.F.Holzman, D.A.Egan, R.Edalji, R.Simmer.
 
  ABSTRACT  
 
Cyclosporin A (CsA), a potent immunosuppressant, is known to bind with high specificity to cyclophilin (CyP), a 17.7 kDa protein with peptidyl-prolyl isomerase activity. In order to investigate the three-dimensional structure of the CsA/CyP complex, we have applied a variety of multidimensional NMR methods in the study of uniformly 13C-labeled CsA bound to cyclophilin. The 1H and 13C NMR signals of cyclosporin A in the bound state have been assigned, and from a quantitative interpretation of the 3D NOE data, the bound conformation of CsA has been determined. Three-dimensional structures of CsA calculated from the NOE data by using a distance geometry/simulated appealing protocol were found to be very different from previously determined crystalline and solution conformations of uncomplexed CsA. In addition, from CsA/CyP NOEs, the portions of CsA that interact with cyclophilin were identified. For the most part, those CsA residues with NOEs to cyclophilin were the same residues important for cyclophilin binding and immunosuppressive activity as determined from structure/activity relationships. The structural information derived in this study together with the known structure/activity relationships for CsA analogues may prove useful in the design of improved immunosuppressants. Moreover, the approach that is described for obtaining the structural information is widely applicable to the study of small molecule/large molecule interactions.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
16372262 P.Ghezzi, S.Casagrande, T.Massignan, M.Basso, E.Bellacchio, L.Mollica, E.Biasini, R.Tonelli, I.Eberini, E.Gianazza, W.W.Dai, M.Fratelli, M.Salmona, B.Sherry, and V.Bonetto (2006).
Redox regulation of cyclophilin A by glutathionylation.
  Proteomics, 6, 817-825.  
15479239 L.M.Henriksson, P.Johansson, T.Unge, and S.L.Mowbray (2004).
X-ray structure of peptidyl-prolyl cis-trans isomerase A from Mycobacterium tuberculosis.
  Eur J Biochem, 271, 4107-4113.
PDB code: 1w74
14976206 L.Volpon, H.Lamthanh, J.Barbier, N.Gilles, J.Molgó, A.Ménez, and J.M.Lancelin (2004).
NMR solution structures of delta-conotoxin EVIA from Conus ermineus that selectively acts on vertebrate neuronal Na+ channels.
  J Biol Chem, 279, 21356-21366.
PDB codes: 1g1p 1g1z
12447904 D.Altschuh (2002).
Cyclosporin A as a model antigen: immunochemical and structural studies.
  J Mol Recognit, 15, 277-285.  
11576329 P.Sedmera, A.Jegorov, M.Buchta, and L.Cvak (2001).
11-Demethylcyclosporins exhibit a single conformation in methanol and dimethylsulfoxide.
  J Pept Res, 58, 229-236.  
9214308 A.Zvi, D.J.Feigelson, Y.Hayek, and J.Anglister (1997).
Conformation of the principal neutralizing determinant of human immunodeficiency virus type 1 in complex with an anti-gp120 virus neutralizing antibody studied by two-dimensional nuclear magnetic resonance difference spectroscopy.
  Biochemistry, 36, 8619-8627.  
  9032343 D.Braaten, H.Ansari, and J.Luban (1997).
The hydrophobic pocket of cyclophilin is the binding site for the human immunodeficiency virus type 1 Gag polyprotein.
  J Virol, 71, 2107-2113.  
9063871 G.Melacini, Q.Zhu, and M.Goodman (1997).
Multiconformational NMR analysis of sandostatin (octreotide): equilibrium between beta-sheet and partially helical structures.
  Biochemistry, 36, 1233-1241.
PDB codes: 1soc 2soc
9119014 H.Ottleben, M.Haasemann, R.Ramachandran, M.Görlach, W.Müller-Esterl, and L.R.Brown (1997).
An NMR study of the interaction of 15N-labelled bradykinin with an antibody mimic of the bradykinin B2 receptor.
  Eur J Biochem, 244, 471-478.  
8541448 M.Marraud, and A.Aubry (1996).
Crystal structures of peptides and modified peptides.
  Biopolymers, 40, 45-83.  
  8877268 Y.Fraenkel, D.E.Shalev, J.M.Gershoni, and G.Navon (1996).
Nuclear magnetic resonance (NMR) analysis of ligand receptor interactions: the cholinergic system--a model.
  Crit Rev Biochem Mol Biol, 31, 273-301.  
  7543589 E.K.Franke, B.X.Chen, I.Tatsis, A.Diamanduros, B.F.Erlanger, and J.Luban (1995).
Cyclophilin binding to the human immunodeficiency virus type 1 Gag polyprotein is mimicked by an anti-cyclosporine antibody.
  J Virol, 69, 5821-5823.  
7749913 J.R.Bagu, F.D.Sönnichsen, D.Williams, R.J.Andersen, B.D.Sykes, and C.F.Holmes (1995).
Comparison of the solution structures of microcystin-LR and motuporin.
  Nat Struct Biol, 2, 114-116.
PDB codes: 1eva 1evb 1evc 1evd
8075536 C.Spitzfaden, W.Braun, G.Wider, H.Widmer, and K.Wüthrich (1994).
Determination of the NMR solution structure of the cyclophilin A-cyclosporin A complex.
  J Biomol NMR, 4, 463-482.
PDB code: 3cys
7866747 D.Altschuh, W.Braun, J.Kallen, V.Mikol, C.Spitzfaden, J.C.Thierry, O.Vix, M.D.Walkinshaw, and K.Wüthrich (1994).
Conformational polymorphism of cyclosporin A.
  Structure, 2, 963-972.  
8075981 H.Ke, D.Mayrose, P.J.Belshaw, D.G.Alberg, S.L.Schreiber, Z.Y.Chang, F.A.Etzkorn, S.Ho, and C.T.Walsh (1994).
Crystal structures of cyclophilin A complexed with cyclosporin A and N-methyl-4-[(E)-2-butenyl]-4,4-dimethylthreonine cyclosporin A.
  Structure, 2, 33-44.
PDB codes: 2rma 2rmb
8041800 H.Kubinyi (1994).
[The key and the lock. I. The basis of drug action]
  Pharm Unserer Zeit, 23, 158-168.  
7773776 H.Liang, X.Mao, E.T.Olejniczak, D.G.Nettesheim, L.Yu, R.P.Meadows, C.B.Thompson, and S.W.Fesik (1994).
Solution structure of the ets domain of Fli-1 when bound to DNA.
  Nat Struct Biol, 1, 871-875.
PDB code: 1fli
7764895 M.W.MacArthur, P.C.Driscoll, and J.M.Thornton (1994).
NMR and crystallography--complementary approaches to structure determination.
  Trends Biotechnol, 12, 149-153.  
8364158 A.Thomas, B.Roux, and J.C.Smith (1993).
Computer simulations of the flexibility of a series of synthetic cyclic peptide analogues.
  Biopolymers, 33, 1249-1270.  
7689806 G.Zenke, G.Baumann, R.Wenger, P.Hiestand, V.Quesniaux, E.Andersen, and M.H.Schreier (1993).
Molecular mechanisms of immunosuppression by cyclosporins.
  Ann N Y Acad Sci, 685, 330-335.  
8265636 H.Ke, Y.Zhao, F.Luo, I.Weissman, and J.Friedman (1993).
Crystal structure of murine cyclophilin C complexed with immunosuppressive drug cyclosporin A.
  Proc Natl Acad Sci U S A, 90, 11850-11854.
PDB code: 2rmc
8102073 K.D.Kopple, J.W.Bean, K.K.Bhandary, J.Briand, C.A.D'Ambrosio, and C.E.Peishoff (1993).
Conformational mobility in cyclic oligopeptides.
  Biopolymers, 33, 1093-1099.  
8460105 O.Vix, B.Rees, J.C.Thierry, and D.Altschuh (1993).
Crystallographic analysis of the interaction between cyclosporin A and the Fab fragment of a monoclonal antibody.
  Proteins, 15, 339-348.  
8483337 R.A.Wiley, and D.H.Rich (1993).
Peptidomimetics derived from natural products.
  Med Res Rev, 13, 327-384.  
7689377 S.W.Fesik (1993).
NMR structure-based drug design.
  J Biomol NMR, 3, 261-269.  
1375171 C.A.Lepre, J.A.Thomson, and J.M.Moore (1992).
Solution structure of FK506 bound to FKBP-12.
  FEBS Lett, 302, 89-96.  
15336050 D.Binge (1992).
Molecular matchmakers.
  Curr Biol, 2, 545-547.  
1384551 J.J.Siekierka, and N.H.Sigal (1992).
FK-506 and cyclosporin A: immunosuppressive mechanism of action and beyond.
  Curr Opin Immunol, 4, 548-552.  
1617685 J.Wu, and A.S.Serianni (1992).
Isotope-edited 1D and 2D n.m.r. spectroscopy of 13C-substituted carbohydrates.
  Carbohydr Res, 226, 209-218.  
  1338979 L.D.Zydowsky, F.A.Etzkorn, H.Y.Chang, S.B.Ferguson, L.A.Stolz, S.I.Ho, and C.T.Walsh (1992).
Active site mutants of human cyclophilin A separate peptidyl-prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition.
  Protein Sci, 1, 1092-1099.  
1483474 M.Gurrath, G.Müller, H.Kessler, M.Aumailley, and R.Timpl (1992).
Conformation/activity studies of rationally designed potent anti-adhesive RGD peptides.
  Eur J Biochem, 210, 911-921.  
1368432 W.J.Chazin (1992).
NMR structures and methodology.
  Curr Opin Biotechnol, 3, 326-332.  
1946361 H.M.Ke, L.D.Zydowsky, J.Liu, and C.T.Walsh (1991).
Crystal structure of recombinant human T-cell cyclophilin A at 2.5 A resolution.
  Proc Natl Acad Sci U S A, 88, 9483-9487.  
1743298 P.Neri, R.Meadows, G.Gemmecker, E.Olejniczak, D.Nettesheim, T.Logan, R.Simmer, R.Helfrich, T.Holzman, and J.Severin (1991).
1H, 13C and 15N backbone assignments of cyclophilin when bound to cyclosporin A (CsA) and preliminary structural characterization of the CsA binding site.
  FEBS Lett, 294, 81-88.  
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.

 

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