Title : Structure of human
neutral endopeptidase (
Neprilysin ) complexed with phosphoramidon
Abstract :
- Neutral endopeptidase is a mammalian type II integral membrane zinc-containing endopeptidase , which degrades and inactivates a number of bioactive peptides
- The range of substrates cleaved by neutral endopeptidase in vitro includes the enkephalins, substance P , endothelin, bradykinin and atrial natriuretic factor
- Due to the physiological importance of neutral endopeptidase in the modulation of nociceptive and pressor responses there is considerable interest in inhibitors of this enzyme as novel analgesics and anti-hypertensive agents
- Here we describe the crystal structure of the extracellular domain ( residues 52-749 ) of human NEP complexed with the generic metalloproteinase inhibitor phosphoramidon at 2.1 A resolution
- The structure reveals two multiply connected folding domains which embrace a large central cavity containing the active site
- The inhibitor is bound to one side of this cavity and its binding mode provides a detailed understanding of the ligand-binding and specificity determinants