2 Å X‐ray structure of adamalysin II complexed with a peptide phosphonate inhibitor adopting a retro‐binding mode

Abstract

The search of reprolysin inhibitors offers the possibility of intervention against both matrixins and ADAMs. Here we report the crystal structure of the complex between adamalysin II, a member of the reprolysin family, and a phosphonate inhibitor modeled on an endogenous venom tripeptide. The inhibitor occupies the primed region of the cleavage site adopting a retro-binding mode. The phosphonate group ligates the zinc ion in an asymmetric bidentate mode and the adjacent Trp indole system partly fills the primary specificity subsite Si'. An adamalysin-based model of tumor necrosis factor-a-converting enzyme (TACE) reveals a smaller Si' pocket for this enzyme.

Role for ADAM-family proteinases as membrane protein secretases

“…The N-terminal region has a prodomain with a 'cysteine switch' and a furin cleavage site, a catalytic domain typical of the metzincin metalloproteinases [22], T h e possible activation of the enzyme by furin-catalysed removal of its prodomain is consistent with previous observations that serine proteinase inhibitors can prevent the release of soluble TNF-a from cells [23]. T h e active-site region of TACE has been modelled on the basis of the structure of adamalysin I1 [24] and, more recently, a 2 A resolution crystal structure of the catalytic domain of TACE itself has proved highly informative [25]. It reveals unique surface features distinct from the known adamalysin structures as well as unique features in the active-site pocket that should aid in the design of selective TACE in hi hi tors.…”

Crystal structure of a non-hemorrhagic fibrin(ogen)olytic metalloproteinase complexed with a novel natural tri-peptide inhibitor from venom of Agkistrodon acutus

“…According to the structure of FII, the S1 pocket is not fulWlled by the Leu-B3 side chain. There are still three ordered water molecules occupying this pocket upon binding of a Leu-containing inhibitor, which is similar to the structure of adamalysin II (Cirilli et al, 1997). The carboxylate oxygen atom of Leu-B3 is located close to the O l and O 2 atoms of the probably protonated Glu l43, with respective distances of 3.62 and 2.83 Å. Glu l43 has been considered to play the role of the general base in the commonly accepted mechanism by which means zinc proteases cleave their protein substrates (Grams et al, 1996;Kester and Matthews, 1977).…”

Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome

“…Searching for the reference proteins and sequence alignments was performed using positionspecific iterated (PSI)-BLAST. 23 The reference proteins were adamalysin II (PDB 24 ID: 4AIG 25 ) for the metalloprotease domain and thrombospondin-1 type 1 repeats (PDB ID: 1LSL 26 ) for Tsp1-5 and Tsp1-8 domains. The sequence alignments produced using PSI-BLAST were manually adjusted taking biologically important regions and secondary structure into consideration using the CHIMERA modeling system.…”