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PDBsum entry 2qds

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protein ligands metals links
Hydrolase PDB id
2qds
Jmol
Contents
Protein chain
225 a.a. *
Ligands
SO4 ×4
MCO
GOL ×2
Metals
_ZN
Waters ×188
* Residue conservation analysis
PDB id:
2qds
Name: Hydrolase
Title: Crystal structure of the zinc carbapenemase cpha in complex inhibitor d-captopril
Structure: Beta-lactamase. Chain: a. Engineered: yes
Source: Aeromonas hydrophila. Organism_taxid: 644. Gene: cpha. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.66Å     R-factor:   0.149     R-free:   0.170
Authors: G.Garau,O.Dideberg
Key ref: B.M.Liénard et al. (2008). Structural basis for the broad-spectrum inhibition of metallo-beta-lactamases by thiols. Org Biomol Chem, 6, 2282-2294. PubMed id: 18563261
Date:
21-Jun-07     Release date:   17-Jul-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P26918  (BLAB_AERHY) -  Beta-lactamase
Seq:
Struc:
254 a.a.
225 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.5.2.6  - Beta-lactamase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Penicillin Biosynthesis and Metabolism
      Reaction: A beta-lactam + H2O = a substituted beta-amino acid
      Cofactor: Zn(2+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     periplasmic space   1 term 
  Biological process     response to antibiotic   2 terms 
  Biochemical function     hydrolase activity     4 terms  

 

 
Org Biomol Chem 6:2282-2294 (2008)
PubMed id: 18563261  
 
 
Structural basis for the broad-spectrum inhibition of metallo-beta-lactamases by thiols.
B.M.Liénard, G.Garau, L.Horsfall, A.I.Karsisiotis, C.Damblon, P.Lassaux, C.Papamicael, G.C.Roberts, M.Galleni, O.Dideberg, J.M.Frère, C.J.Schofield.
 
  ABSTRACT  
 
The development of broad-spectrum metallo-beta-lactamase (MBL) inhibitors is challenging due to structural diversity and differences in metal utilisation by these enzymes. Analysis of structural data, followed by non-denturing mass spectrometric analyses, identified thiols proposed to inhibit representative MBLs from all three sub-classes: B1, B2 and B3. Solution analyses led to the identification of broad spectrum inhibitors, including potent inhibitors of the CphA MBL (Aeromonas hydrophila). Structural studies revealed that, as observed for other B1 and B3 MBLs, inhibition of the L1 MBL thiols involves metal chelation. Evidence is reported that this is not the case for inhibition of the CphA enzyme by some thiols; the crystal structure of the CphA-Zn-inhibitor complex reveals a binding mode in which the thiol does not interact with the zinc. The structural data enabled the design and the production of further more potent inhibitors. Overall the results suggest that the development of reasonably broad-spectrum MBL inhibitors should be possible.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20394454 C.Bebrone, P.Lassaux, L.Vercheval, J.S.Sohier, A.Jehaes, E.Sauvage, and M.Galleni (2010).
Current challenges in antimicrobial chemotherapy: focus on ß-lactamase inhibition.
  Drugs, 70, 651-679.  
20088513 N.R.Rose, E.C.Woon, G.L.Kingham, O.N.King, J.Mecinović, I.J.Clifton, S.S.Ng, J.Talib-Hardy, U.Oppermann, M.A.McDonough, and C.J.Schofield (2010).
Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches.
  J Med Chem, 53, 1810-1818.
PDB code: 2wwj
20121112 P.Oelschlaeger, N.Ai, K.T.Duprez, W.J.Welsh, and J.H.Toney (2010).
Evolving carbapenemases: can medicinal chemists advance one step ahead of the coming storm?
  J Med Chem, 53, 3013-3027.  
20065329 S.M.Drawz, and R.A.Bonomo (2010).
Three decades of beta-lactamase inhibitors.
  Clin Microbiol Rev, 23, 160-201.  
19651913 C.Bebrone, H.Delbrück, M.B.Kupper, P.Schlömer, C.Willmann, J.M.Frère, R.Fischer, M.Galleni, and K.M.Hoffmann (2009).
The structure of the dizinc subclass B2 metallo-beta-lactamase CphA reveals that the second inhibitory zinc ion binds in the histidine site.
  Antimicrob Agents Chemother, 53, 4464-4471.
PDB codes: 3f9o 3fai
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 code is shown on the right.