Structures of adamalysin II with peptidic inhibitors. Implications for the design of tumor necrosis factor α convertase inhibitors

Crotalus adamanteus snake venom adamalysin II is the structural prototype of the adamalysin or ADAM family comprising proteolytic domains of snake venom metalloproteinases, multimodular mammalian reproductive tract proteins, and tumor necrosis factor α convertase, TACE, involved in the release of th...

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Bibliographic Details
Published in:Protein science 1998-02, Vol.7 (2), p.283-292
Main Authors: Xavier Gomis‐Rüth, F., Meyer, Edgar F., Kress, Lawrence F., Politi, Vincenzo
Format: Article
Language:English
Subjects:
ADAM
ADAM Proteins
ADAM17 Protein
adamalysin
Crotalid Venoms - chemistry
Drug Design
Enzyme Inhibitors - chemistry
Humans
Metalloendopeptidases - antagonists & inhibitors
Metalloendopeptidases - chemistry
Peptides - chemistry
Protein Conformation
Sequence Homology, Amino Acid
snake venom prokinase
X-Ray Diffraction
X‐ray structure
zine endopeptidase
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Summary:Crotalus adamanteus snake venom adamalysin II is the structural prototype of the adamalysin or ADAM family comprising proteolytic domains of snake venom metalloproteinases, multimodular mammalian reproductive tract proteins, and tumor necrosis factor α convertase, TACE, involved in the release of the inflammatory cytokine, TNFα. The structure of adamalysin II in noncovalent complex with two small‐molecule right‐hand side peptidomimetic inhibitors (Pol 647 and Pol 656) has been solved using X‐ray diffraction data up to 2.6 and 2.8 Å resolution. The inhibitors bind to the ‐side of the proteinase, inserting between two protein segments, establishing a mixed parallel‐antiparallel three‐stranded β‐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 other known structures. An adamalysin‐based model of the active site of TACE reveals that these small molecules would probably fit into the active site cleft of this latter metalloproteinase, providing a starting model for the rational design of TACE inhibitors.
ISSN:0961-8368
1469-896X
DOI:10.1002/pro.5560070207