7tln

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spinqualitylabelsall models 7tln, resolution 2.3Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

STRUCTURAL ANALYSIS OF THE INHIBITION OF THERMOLYSIN BY AN ACTIVE-SITE-DIRECTED IRREVERSIBLE INHIBITOR

Overview

The mode of binding of the irreversible thermolysin inhibitor, ClCH2CO-DL-(N-OH)Leu-OCH3 [Rasnick, D., & Powers, J.C. (1978) Biochemistry, 17, 4363-4369] has been determined by X-ray crystallography at a, resolution of 2.3 A and the structure of the covalent complex refined to, give a crystallographic residual of 17.0%. This is the first such, structural study of an active-site-directed covalent complex of a zinc, protease. As anticipated by Rasnick and Powers, the inhibitor alkylates, Glu-143 in the thermolysin active site, and the hydroxamic acid moiety, coordinates the zinc ion. The formation of the covalent complex is, associated with a significant shift in a segment of the polypeptide, backbone in the vicinity of the active site. This conformational, adjustment appears to be necessary to relieve steric hindrance which would, otherwise prevent alkylation of Glu-143. It is suggested that this steric, hindrance, which occurs for thermolysin but would not be expected for, carboxypeptidase A, accounts for the previously inexplicable difference in, reactivity of these two metalloproteases toward N-haloacetyl amino acids., The relevance of this steric hindrance to the mechanism of catalysis is, discussed. In agreement with previous results [Kester, W. R., & Matthews, B. W. (1977) Biochemistry 16, 2506-2516], it appears that steric hindrance, prevents the direct attack of Glu-143 on the carbonyl carbon of an, extended substrate, therefore ruling out the anhydride pathway in, thermolysin-catalyzed hydrolysis of polypeptide substrates and their ester, analogues.

About this Structure

7TLN is a Single protein structure of sequence from Bacillus thermoproteolyticus with CA, ZN and INC as ligands. This structure superseeds the now removed PDB entry 6TLN. Active as Thermolysin, with EC number 3.4.24.27 Full crystallographic information is available from OCA.

Reference

Structural analysis of the inhibition of thermolysin by an active-site-directed irreversible inhibitor., Holmes MA, Tronrud DE, Matthews BW, Biochemistry. 1983 Jan 4;22(1):236-40. PMID:6830761

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