1IY7

Crystal Structure of CPA and sulfamide-based inhibitor complex

Summary for 1IY7

• Entry DOI: 10.2210/pdb1iy7/pdb
• Descriptor: Carboxypeptidase A, ZINC ION, PHENYLALANINE-N-SULFONAMIDE, ... (4 entities in total)
• Functional Keywords: protein-inhibitor complex, hydrolase
• Biological source: Bos taurus (cattle)
• Cellular location: Secreted, extracellular space: P00730
• Total number of polymer chains: 1
• Total formula weight: 34752.14

Authors

Kim, S.J.,Woo, J.R.,Park, J.D.,Kim, D.H.,Ryu, S.E. (deposition date: 2002-07-24, release date: 2003-01-28, Last modification date: 2024-10-23)

Primary citation

Park, J.D.,Kim, D.H.,Kim, S.J.,Woo, J.R.,Ryu, S.E.
Sulfamide-Based Inhibitors for Carboxypeptidase A. Novel Type Transition State Analogue Inhibitors for Zinc Proteases
J.Med.Chem., 45:5295-5302, 2002

PubMed Abstract: 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.

PubMed: 12431056
DOI: 10.1021/jm020258v

Experimental method

X-RAY DIFFRACTION (2 Å)