Conformation of ethyl (+)-(2S,3S)-3-{1-[N-(3-methylbutyl)amino]leucylcarbonyl}oxi-rane-2-carboxylate (loxistatin), a cysteine protease inhibitor: X-ray crystallographic and 1H nuclear magnetic resonance studies

Abstract

In order to establish the conformational characteristics of a cysteine protease inhibitor, the crystal and solution conformations of loxistatin have been determined by X-ray crystallographic and ¹H n.m.r. spectroscopic analyses. The molecules were arranged in the crystal as a series of infinite parallel β-sheet structures formed via intermolecular N-H ⋯ O hydrogen bonds. The loxistatin molecule has a flattened, curved conformation, which appears to be energetically stable. Similar conformations of loxistatin were also observed in (CD₃)₂SO and CDCl₃ solutions. On the basis of the results obtained, the relation between the conformation of loxistatin and its inhibitory activity was discussed and compared with the stereostructure of the papain–substrate analogue complex.