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.
A three-dimensional construction of the active site (region 507-749) of human neutral endopeptidase (EC.3.4.24.11).,Tiraboschi G, Jullian N, Thery V, Antonczak S, Fournie-Zaluski MC, Roques BP Protein Eng. 1999 Feb;12(2):141-9. PMID:10195285[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑ Tiraboschi G, Jullian N, Thery V, Antonczak S, Fournie-Zaluski MC, Roques BP. A three-dimensional construction of the active site (region 507-749) of human neutral endopeptidase (EC.3.4.24.11). Protein Eng. 1999 Feb;12(2):141-9. PMID:10195285
