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PDBsum entry 1cyb
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Immunosuppressant
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PDB id
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1cyb
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References listed in PDB file
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Key reference
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Title
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Nmr studies of [u-13c]cyclosporin a bound to cyclophilin: bound conformation and portions of cyclosporin involved in binding.
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Authors
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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.
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Ref.
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Biochemistry, 1991,
30,
6574-6583.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Secondary reference #1
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Title
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Identification of solvent-Exposed regions of enzyme-Bound ligands by nuclear magnetic resonance
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Authors
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S.W.Fesik,
G.Gemmecker,
E.T.Olejniczak,
A.M.Petros.
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Ref.
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j am chem soc, 1991,
113,
7080.
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Secondary reference #2
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Title
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1h, 13c and 15n backbone assignments of cyclophilin when bound to cyclosporin a (csa) and preliminary structural characterization of the csa binding site.
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Authors
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P.Neri,
R.Meadows,
G.Gemmecker,
E.Olejniczak,
D.Nettesheim,
T.Logan,
R.Simmer,
R.Helfrich,
T.Holzman,
J.Severin.
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Ref.
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FEBS Lett, 1991,
294,
81-88.
[DOI no: ]
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PubMed id
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