A three-dimensional construction of the active site (region 507749) of human neutral endopeptidase (EC.3.4.24.11) |
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Authors: | Tiraboschi, Gilles Jullian, Nathalie Thery, Vincent Antonczak, Serge Fournie-Zaluski, Marie-Claude Roques, Bernard P. |
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Affiliation: | 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 |
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Abstract: | A three-dimensional model of the 507749 region of neutralendopeptidase-24.11 (NEP; E.C.3.4.24.11) was constructed integratingthe results of secondary structure predictions and sequencehomologies with the bacterial endopeptidase thermolysin. Additionaldata were extracted from the structure of two other metalloproteases,astacin and stromelysin. The resulting model accounts for themain biological properties of NEP and has been used to describethe environment close to the zinc atom defining the catalyticsite. The analysis of several thiol inhibitors, complexed inthe model active site, revealed the presence of a large hydrophobicpocket at the S1' subsite level. This is supported by the natureof the constitutive amino acids. The computed energies of boundinhibitors correspond with the relative affinities of the stereoisomersof benzofused macrocycle derivatives of thiorphan. The modelcould be used to facilitate the design of new NEP inhibitors,as illustrated in the paper. |
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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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