MOLECULAR MODELING OF THE ACTIVE-SITE OF ENDOTHELIN-CONVERTING ENZYME

Endothelin-converting enzyme (ECE) is a member of the zinc metalloprot einase family. It is much more specific in its protease activity than the bacterial metalloprotease thermolysin; we aim to construct a model of its active site to help to explain these differences. We aligned t he sequence of human ECE with those of human neprilysin (which is 39% identical to ECE) and thermolysin. Residues believed to be important f or inhibitor binding were assigned from the alignment and by analogy w ith structural and functional studies of these enzymes. These included a conserved IGG motif N-terminal to the zinc-binding HExxH motif, and a tyrosine residue that may be analogous to Y157 of thermolysin. We h ave used the program O to build a model of the active site of ECE base d on the crystal structure of thermolysin.