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Title
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Crystal structure of an actinidin-E-64 complex.
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Authors
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K.I.Varughese,
Y.Su,
D.Cromwell,
S.Hasnain,
N.H.Xuong.
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Ref.
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Biochemistry, 1992,
31,
5172-5176.
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PubMed id
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Abstract
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E-64, 1-(L-trans-epoxysuccinylleucylamino)-4-guanidinobutane, is a potent and
highly selective irreversible inhibitor of cysteine proteases. The crystal
structure of a complex of actinidin and E-64 has been determined at 1.86-A
resolution by using the difference Fourier method and refined to an R-factor of
14.5%. The electron density map clearly shows that the C2 atom of the E-64
epoxide ring is covalently bonded to the S atom of the active-site cysteine 25.
The charged carboxyl group of E-64 forms four H-bonds with the protein and thus
may play an important role in favorably positioning the inhibitor molecule for
nucleophilic attack by the active-site thiolate anion. The interaction features
between E-64 and actinidin are very similar to those seen in the papain-E-64
complex; however, the amino-4-guanidinobutane group orients differently. The
crystals of the actinidin-E-64 complex diffracted much better than the
papain-E-64 complex, and consequently the present study provides more precise
geometrical information on the binding of the inhibitor. Moreover, this study
provides yet another confirmation that the binding of E-64 is at the S subsites
and not at the S' subsites as has been previously proposed. The original
actinidin structure has been revised using the new cDNA sequence information.
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