A comparison between the binding modes of a substrate and inhibitor to papain as observed in complex crystal structures.
On the basis of the crystal structures of papain complexed with the substrate analogue benzyloxycarbonyl-L-phenylalanyl-L-alanine chloromethyl-ketone (Drenth, J., Kalk, K.H., and Swen, H.M. (1976) Biochemistry 15, 3731-3738) and with the inhibitor E-64-c, the binding modes were compared at the atomic level to clarify the functional difference between the substrate and inhibitor. Irrespective of the reverse chemical bonding in the peptide bonds, both the molecules are located at the S subsites of papain with similar interactions. However, the inhibitory activity of E-64-c is characterized by the stereochemical function of a carboxyoxirane ring and the tight binding of the isopentylaminoleucyl side chain to the S subsites.
Department of Physical Chemistry, Osaka University of Pharmaceutical Sciences, Japan.
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Yamamoto
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Ishida
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Inoue
D000590:Amino Acid Chloromethyl Ketones / Q000378:metabolism*; D001665:Binding Sites; D003460:Crystallization; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism*; D007930:Leucine / Q000031:analogs & derivatives* / Q000378:metabolism; D008958:Models, Molecular; D010206:Papain / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D014961:X-Ray Diffraction
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; C065676:benzyloxycarbonylphenylalanyl-alanine chloromethyl ketone; C032425:N-(N-(3-carboxyoxirane-2-carbonyl)leucyl)isoamylamine; D010206:Papain; D007930:Leucine