1tmn
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(New page: 200px<br /><applet load="1tmn" size="450" color="white" frame="true" align="right" spinBox="true" caption="1tmn, resolution 1.9Å" /> '''BINDING OF N-CARBOXYM...)
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BINDING OF N-CARBOXYMETHYL DIPEPETIDE INHIBITORS TO THERMOLYSIN DETERMINED BY X-RAY CRYSTALLOGRAPHY. A NOVEL CLASS OF TRANSITION-STATE ANALOGUES FOR ZINC PEPTIDASES
Overview
The mode of binding of the specific thermolysin inhibitor, N-(1-carboxy-3-phenylpropyl)-L-leucyl-L-tryptophan (KI approximately 5 X, 10(-8) M) [Maycock, A. L., DeSousa, D. M., Payne, L. G., ten Broeke, J., Wu, M. T., & Patchett, A. A. (1981) Biochem. Biophys. Res. Commun. 102, 963-969] has been determined by X-ray crystallography and refined to an R, value of 17.1% at 1.9-A resolution. The inhibitor binds to thermolysin, with both oxygens of the N-carboxymethyl group liganded to the zinc to, give overall pentacoordination of the metal. The bidentate ligation of the, inhibitor differs from the monodentate binding seen previously for, carboxylate-zinc interactions in thermolysin and is closer to the, bidentate geometry observed for the binding of hydroxamates [Holmes, M., A., & Matthews, B. W. (1981) Biochemistry 20, 6912-6920]. The geometry of, the inhibitor and its interactions with the protein have a number of, elements in common with the presumed transition state formed during, peptide hydrolysis. The observed zinc ligation supports the previous, suggestion that a pentacoordinate intermediate participates in the, mechanism of catalysis. However, the alpha-amino nitrogen of the inhibitor, is close to Glu-143, suggesting that this residue might accept a proton, from an attacking water molecule (as proposed before) and subsequently, donate this proton to the leaving nitrogen. By analogy with thermolysin, it is proposed that a related mechanism should be considered for peptide, cleavage by carboxypeptidase A.(ABSTRACT TRUNCATED AT 250 WORDS)
About this Structure
1TMN is a Single protein structure of sequence from [1] with CA and ZN as ligands. Active as Thermolysin, with EC number 3.4.24.27 Full crystallographic information is available from OCA.
Reference
Binding of N-carboxymethyl dipeptide inhibitors to thermolysin determined by X-ray crystallography: a novel class of transition-state analogues for zinc peptidases., Monzingo AF, Matthews BW, Biochemistry. 1984 Nov 20;23(24):5724-9. PMID:6395881
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