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Title
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The X-ray structure of (MeBm2t)1-cyclosporin complexed with cyclophilin A provides an explanation for its anomalously high immunosuppressive activity.
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Authors
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V.Mikol,
J.Kallen,
M.D.Walkinshaw.
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Ref.
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Protein Eng, 1994,
7,
597-603.
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PubMed id
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Abstract
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For most of the cyclosporin A (CsA) analogs, there is generally a good
correlation between cyclophilin binding and immunosuppression. However, this
relationship does not seem to hold for
4-[(E)-2-butenyl]-4,4,N-trimethyl-L-threonine1 (MeBm2t)1-CsA. Its affinity for
cyclophilin was reported to be approximately 1% that of CsA and its
immunosuppressive activity in vitro was shown to be approximately 30% that of
CsA. We report here the crystal structure of a complex between recombinant human
cyclophilin A (CypA) and (MeBm2t)1-CsA which has been determined by X-ray
crystallography at 2.2 A resolution and refined to an R-factor of 16.3%.
(MeBm2t)1-CsA shows a similar bound conformation and network of interactions to
CypA as CsA. The measured lower affinity for CypA cannot therefore be explained
by a different mode of binding. We propose that the poor affinity to CypA could
be accounted for by the existence of an equilibrium in aqueous solution between
a 'cyclophilin bound conformation' and a 'non-binding conformation' of
(MeBm2t)1-CsA. The relatively high immunosuppressive activity is suggested to
result from slight conformational differences observed in the effector domain.
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