1iy7

From Proteopedia

Revision as of 15:38, 20 November 2007

Crystal Structure of CPA and sulfamide-based inhibitor complex

Overview

N-Sulfamoylphenylalanine and its derivatives having varied alkyl groups on, the terminal amino group were designed rationally as transition state, analogue inhibitors for carboxypeptidase A (CPA) and synthesized. In CPA, inhibitory assays the parent compound having the (S)-configuration, i.e., (S)-1a, showed potent inhibitory activity with the K(i) value of 0.64, microM. Its enantiomer was shown to be much less potent (K(i) = 470, microM). Introduction of an alkyl group such as methyl or isopropyl group, on the terminal amino group of (S)-1a lowered the inhibitory potency, drastically. Introduction of a methyl group on the internal amino group of, (S)-1a also caused a drastic reduction of the inhibitory activity. The, structure of the CPA x(S)-1a complex determined by single-crystal X-ray, diffraction reveals that the sulfamoyl moiety interacts with the zinc ion, and functional groups at the active site of CPA, which is reminiscent of, the postulated stabilization mode of a tetrahedral transition state in the, CPA-catalyzed hydrolysis of a peptide substrate. On the basis of the, design rationale and the binding mode of (S)-1a to CPA shown by X-ray, crystallographic analysis, the present inhibitors are inferred to be a, novel type of transition state analogue inhibitor for CPA.

About this Structure

1IY7 is a Single protein structure of sequence from Bos taurus with ZN and CXA as ligands. Active as Carboxypeptidase A, with EC number 3.4.17.1 Full crystallographic information is available from OCA.

Reference

Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases., Park JD, Kim DH, Kim SJ, Woo JR, Ryu SE, J Med Chem. 2002 Nov 21;45(24):5295-302. PMID:12431056

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