Protein Engineering, Vol. 12, No. 2, 141-149,
February 1999
© 1999 Oxford University Press
A three-dimensional construction of the active site (region 507–749) of human neutral endopeptidase (EC.3.4.24.11)
Département de Pharmacochimie Moléculaire et Structurale, INSERM U266, CNRS URA D1500, UFR des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75270 Paris, Cedex 06, 1 Molecular Simulations SARL, Parc Club Orsay Université, 20 Rue Jean Rostand, 91893 Orsay Cedex, 2 Laboratoire de Synthèse Organique, Faculté de Sciences, Les Cézeaux, 63177 Aubiere and 3 Laboratoire de Chimie Théorique, CNRS URA 510, Université Nancy 1, BP 239, Domaine Universitaire Victor-Grignard, 54506 Vandoeuvre-Les-Nancy Cedex, France
A three-dimensional model of the 507–749 region of neutral endopeptidase-24.11 (NEP; E.C.3.4.24.11) was constructed integrating the results of secondary structure predictions and sequence homologies with the bacterial endopeptidase thermolysin. Additional data were extracted from the structure of two other metalloproteases, astacin and stromelysin. The resulting model accounts for the main biological properties of NEP and has been used to describe the environment close to the zinc atom defining the catalytic site. The analysis of several thiol inhibitors, complexed in the model active site, revealed the presence of a large hydrophobic pocket at the S1' subsite level. This is supported by the nature of the constitutive amino acids. The computed energies of bound inhibitors correspond with the relative affinities of the stereoisomers of benzofused macrocycle derivatives of thiorphan. The model could be used to facilitate the design of new NEP inhibitors, as illustrated in the paper.
Keywords: zinc metallopeptidase/homology modelling/secondary structure prediction/sequence alignment/enzyme active-site/S1' subsite modeling/enzyme inhibitor complex/thiorphan/disulfide bridge/structure refinement
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