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1iy7
From Proteopedia
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| , resolution 2.00Å | |||||||
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| Ligands: | , | ||||||
| Activity: | Carboxypeptidase A, with EC number 3.4.17.1 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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. 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
Page seeded by OCA on Sun Mar 30 21:26:17 2008
