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PDBsum entry 1iy7

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protein ligands metals links
Hydrolase PDB id
1iy7
Jmol
Contents
Protein chain
307 a.a. *
Ligands
CXA
Metals
_ZN
Waters ×148
* Residue conservation analysis
PDB id:
1iy7
Name: Hydrolase
Title: Crystal structure of cpa and sulfamide-based inhibitor complex
Structure: Carboxypeptidase a. Chain: a. Engineered: yes
Source: Bos taurus. Cattle. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.00Å     R-factor:   0.175     R-free:   0.208
Authors: S.J.Kim,J.R.Woo,J.D.Park,D.H.Kim,S.E.Ryu
Key ref: J.D.Park et al. (2002). Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases. J Med Chem, 45, 5295-5302. PubMed id: 12431056 DOI: 10.1021/jm020258v
Date:
24-Jul-02     Release date:   28-Jan-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00730  (CBPA1_BOVIN) -  Carboxypeptidase A1
Seq:
Struc:
419 a.a.
307 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 9 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.4.17.1  - Carboxypeptidase A.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Peptidyl-L-amino acid + H2O = peptide + L-amino acid

+
=
+
      Cofactor: Zn(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     zinc ion binding     2 terms  

 

 
    Added reference    
 
 
DOI no: 10.1021/jm020258v J Med Chem 45:5295-5302 (2002)
PubMed id: 12431056  
 
 
Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases.
J.D.Park, D.H.Kim, S.J.Kim, J.R.Woo, S.E.Ryu.
 
  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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
18219114 M.Adler, B.Buckman, J.Bryant, Z.Chang, K.Chu, K.Emayan, P.Hrvatin, I.Islam, J.Morser, D.Sukovich, C.West, S.Yuan, and M.Whitlow (2008).
Structures of potent selective peptide mimetics bound to carboxypeptidase B.
  Acta Crystallogr D Biol Crystallogr, 64, 149-157.
PDB codes: 2piy 2piz 2pj0 2pj1 2pj2 2pj3 2pj4 2pj5 2pj6 2pj7 2pj8 2pj9 2pja 2pjb 2pjc
18437247 K.Devanathan, J.A.Bell, P.C.Wilkins, H.K.Jacobs, and A.S.Gopalan (2007).
Synthetic methodology for the preparation of N-hydroxysulfamides.
  Tetrahedron Lett, 48, 8029-8033.  
17334823 K.H.Kim (2007).
Outliers in SAR and QSAR: is unusual binding mode a possible source of outliers?
  J Comput Aided Mol Des, 21, 63-86.  
17942689 L.Qiu, M.Prashad, B.Hu, K.Prasad, O.Repic, T.J.Blacklock, F.Y.Kwong, S.H.Kok, H.W.Lee, and A.S.Chan (2007).
Enantioselective hydrogenation of alpha-aminomethylacrylates containing a free NH group for the synthesis of beta-amino acid derivatives.
  Proc Natl Acad Sci U S A, 104, 16787-16792.  
17324932 L.Xu, Y.Chong, I.Hwang, A.D'Onofrio, K.Amore, G.P.Beardsley, C.Li, A.J.Olson, D.L.Boger, and I.A.Wilson (2007).
Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase.
  J Biol Chem, 282, 13033-13046.
PDB codes: 2b0w 2b1g 2b1i 2iu0 2iu3
16710859 J.Y.Winum, A.Scozzafava, J.L.Montero, and C.T.Supuran (2006).
Therapeutic potential of sulfamides as enzyme inhibitors.
  Med Res Rev, 26, 767-792.  
20141508 J.Y.Winum, A.Scozzafava, J.L.Montero, and C.T.Supuran (2006).
The sulfamide motif in the design of enzyme inhibitors.
  Expert Opin Ther Pat, 16, 27-47.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.