STRUCTURES OF ADAMALYSIN-II WITH PEPTIDIC INHIBITORS - IMPLICATIONS FOR THE DESIGN OF TUMOR-NECROSIS-FACTOR-ALPHA CONVERTASE INHIBITORS

Crotalus adamanteus snake venom adamalysin II is the structural protot ype of the adamalysin or ADAM family comprising proteolytic domains of snake venom metalloproteinases, multimodular mammalian reproductive t ract proteins, and tumor necrosis factor alpha convertase, TACE, invol ved in the release of the inflammatory cytokine, TNF alpha. The struct ure of adamalysin II in noncovalent complex with two small-molecule ri ght-hand side peptidomimetic inhibitors (Pol 647 and Pol 656) has been solved using X-ray diffraction data up to 2.6 and 2.8 Angstrom resolu tion. The inhibitors bind to the S'-side of the proteinase, inserting between two protein segments, establishing a mixed parallel-antiparall el three-stranded beta-sheet and coordinate the central zinc ion in a bidentate manner via their two C-terminal oxygen atoms. The proteinase -inhibitor complexes are described in detail and are compared with oth er known structures. An adamalysin-based model of the active site of T ACE reveals that these small molecules would probably fit into the act ive site cleft of this latter metalloproteinase, providing a starting model for the rational design of TACE inhibitors.