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PDBsum entry 1l2s
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Hydrolase PDB id
1l2s

 

 

 

 

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Contents
Protein chains
355 a.a. *
Ligands
STC ×3
Waters ×352
* Residue conservation analysis
PDB id:
1l2s
Name: Hydrolase
Title: X-ray crystal structure of ampc beta-lactamase from e. Coli in complex with a dock-predicted non-covalent inhibitor
Structure: Beta-lactamase. Chain: a, b. Synonym: ampc, cephalosporinase. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562. Gene: k12. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.94Å     R-factor:   0.173     R-free:   0.207
Authors: R.A.Powers,F.Morandi,B.K.Shoichet
Key ref:
R.A.Powers et al. (2002). Structure-based discovery of a novel, noncovalent inhibitor of AmpC beta-lactamase. Structure, 10, 1013-1023. PubMed id: 12121656 DOI: 10.1016/S0969-2126(02)00799-2
Date:
24-Feb-02     Release date:   17-Jul-02    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00811  (AMPC_ECOLI) -  Beta-lactamase from Escherichia coli (strain K12)
Seq:
Struc: 		377 a.a.
355 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+)

 

 
DOI no: 10.1016/S0969-2126(02)00799-2 Structure 10:1013-1023 (2002)
PubMed id: 12121656  
 
 
Structure-based discovery of a novel, noncovalent inhibitor of AmpC beta-lactamase.
R.A.Powers, F.Morandi, B.K.Shoichet.
 
  ABSTRACT  
 
beta-lactamases are the most widespread resistance mechanisms to beta-lactam antibiotics, and there is a pressing need for novel, non-beta-lactam drugs. A database of over 200,000 compounds was docked to the active site of AmpC beta-lactamase to identify potential inhibitors. Fifty-six compounds were tested, and three had K(i) values of 650 microM or better. The best of these, 3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid, was a competitive noncovalent inhibitor (K(i) = 26 microM), which also reversed resistance to beta-lactams in bacteria expressing AmpC. The structure of AmpC in complex with this compound was determined by X-ray crystallography to 1.94 A and reveals that the inhibitor interacts with key active-site residues in sites targeted in the docking calculation. Indeed, the experimentally determined conformation of the inhibitor closely resembles the prediction. The structure of the enzyme-inhibitor complex presents an opportunity to improve binding affinity in a novel series of inhibitors discovered by structure-based methods.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Comparison of the Chemical Structures of Several b-Lactamase Ligands(A) Ampicillin, a b-lactamase substrate.(B) Ceftazidime, a b-lactamase-resistant molecule. The R1 side chain ubiquitous among b-lactams is labeled.(C) A boronic acid transition-state analog inhibitor that contains the R1 side chain from ceftazidime [9].(D) Compound 1, 3-[(4-chloroanilino) sulfonyl]thiophene-2-carboxylic acid, a novel, competitive inhibitor of b-lactamase.
 
  The above figure is reprinted by permission from Cell Press: Structure (2002, 10, 1013-1023) copyright 2002.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21524585 Z.Xiao, R.Duan, W.Cui, Y.Zhang, S.Zhang, F.Chen, Y.Zhang, J.Liu, D.Zhang, Y.Meng, L.Wang, and H.Wang (2011).
Synthesis and evaluation of new carbonic anhydrase inhibitors.
  Bioorg Med Chem, 19, 3221-3228.  
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.  
20405927 J.Carlsson, L.Yoo, Z.G.Gao, J.J.Irwin, B.K.Shoichet, and K.A.Jacobson (2010).
Structure-based discovery of A2A adenosine receptor ligands.
  J Med Chem, 53, 3748-3755.  
20065329 S.M.Drawz, and R.A.Bonomo (2010).
Three decades of beta-lactamase inhibitors.
  Clin Microbiol Rev, 23, 160-201.  
20519201 Y.F.Chen, K.C.Hsu, S.R.Lin, W.C.Wang, Y.C.Huang, and J.M.Yang (2010).
SiMMap: a web server for inferring site-moiety map to recognize interaction preferences between protein pockets and compound moieties.
  Nucleic Acids Res, 38, W424-W430.  
19325878 J.H.Lee, S.H.Jeong, S.S.Cha, and S.H.Lee (2009).
New disturbing trend in antimicrobial resistance of gram-negative pathogens.
  PLoS Pathog, 5, e1000221.  
19015328 J.Hosokawa-Muto, Y.O.Kamatari, H.K.Nakamura, and K.Kuwata (2009).
Variety of antiprion compounds discovered through an in silico screen based on cellular-form prion protein structure: Correlation between antiprion activity and binding affinity.
  Antimicrob Agents Chemother, 53, 765-771.  
19305397 Y.Chen, and B.K.Shoichet (2009).
Molecular docking and ligand specificity in fragment-based inhibitor discovery.
  Nat Chem Biol, 5, 358-364.
PDB codes: 3g2y 3g2z 3g30 3g31 3g32 3g34 3g35
18280498 A.P.Graves, D.M.Shivakumar, S.E.Boyce, M.P.Jacobson, D.A.Case, and B.K.Shoichet (2008).
Rescoring docking hit lists for model cavity sites: predictions and experimental testing.
  J Mol Biol, 377, 914-934.
PDB codes: 2ray 2raz 2rb0 2rb1 2rb2 2rbn 2rbo 2rbp 2rbq 2rbr 2rbs 2rbt 2rbu 2rbv 2rbw 2rbx 2rby 2rbz 2rc0 2rc1 2rc2
18338225 J.H.Hsieh, X.S.Wang, D.Teotico, A.Golbraikh, and A.Tropsha (2008).
Differentiation of AmpC beta-lactamase binders vs. decoys using classification kNN QSAR modeling and application of the QSAR classifier to virtual screening.
  J Comput Aided Mol Des, 22, 593-609.  
18713893 J.M.Sonner (2008).
A hypothesis on the origin and evolution of the response to inhaled anesthetics.
  Anesth Analg, 107, 849-854.  
18082409 K.Murano, T.Yamanaka, A.Toda, H.Ohki, S.Okuda, K.Kawabata, K.Hatano, S.Takeda, H.Akamatsu, K.Itoh, K.Misumi, S.Inoue, and T.Takagi (2008).
Structural requirements for the stability of novel cephalosporins to AmpC beta-lactamase based on 3D-structure.
  Bioorg Med Chem, 16, 2261-2275.  
18713898 L.Yang, and J.M.Sonner (2008).
Anesthetic-like modulation of receptor function by surfactants: a test of the interfacial theory of anesthesia.
  Anesth Analg, 107, 868-874.  
17561511 M.Kalp, A.Sheri, J.D.Buynak, C.R.Bethel, R.A.Bonomo, and P.R.Carey (2007).
Efficient inhibition of class A and class D beta-lactamases by Michaelis complexes.
  J Biol Chem, 282, 21588-21591.  
15916423 A.P.Graves, R.Brenk, and B.K.Shoichet (2005).
Decoys for docking.
  J Med Chem, 48, 3714-3728.
PDB code: 1xep
16101414 D.M.Lorber, and B.K.Shoichet (2005).
Hierarchical docking of databases of multiple ligand conformations.
  Curr Top Med Chem, 5, 739-749.  
15651033 E.Bindewald, and J.Skolnick (2005).
A scoring function for docking ligands to low-resolution protein structures.
  J Comput Chem, 26, 374-383.  
16170052 R.Brenk, J.J.Irwin, and B.K.Shoichet (2005).
Here be dragons: docking and screening in an uncharted region of chemical space.
  J Biomol Screen, 10, 667-674.  
15602552 B.K.Shoichet (2004).
Virtual screening of chemical libraries.
  Nature, 432, 862-865.  
15288245 J.C.Alvarez (2004).
High-throughput docking as a source of novel drug leads.
  Curr Opin Chem Biol, 8, 365-370.  
14522049 A.C.Anderson (2003).
The process of structure-based drug design.
  Chem Biol, 10, 787-797.  
12951239 J.Alba, C.Bauvois, Y.Ishii, M.Galleni, K.Masuda, M.Ishiguro, M.Ito, J.M.Frere, and K.Yamaguchi (2003).
A detailed kinetic study of Mox-1, a plasmid-encoded class C beta-lactamase.
  FEMS Microbiol Lett, 225, 183-188.  
12876313 S.D.Goldberg, W.Iannuccilli, T.Nguyen, J.Ju, and V.W.Cornish (2003).
Identification of residues critical for catalysis in a class C beta-lactamase by combinatorial scanning mutagenesis.
  Protein Sci, 12, 1633-1645.  
12676933 S.Soelaiman, B.Q.Wei, P.Bergson, Y.S.Lee, Y.Shen, M.Mrksich, B.K.Shoichet, and W.J.Tang (2003).
Structure-based inhibitor discovery against adenylyl cyclase toxins from pathogenic bacteria that cause anthrax and whooping cough.
  J Biol Chem, 278, 25990-25997.  
12133718 B.K.Shoichet, S.L.McGovern, B.Wei, and J.J.Irwin (2002).
Lead discovery using molecular docking.
  Curr Opin Chem Biol, 6, 439-446.  
12415248 J.Bajorath (2002).
Integration of virtual and high-throughput screening.
  Nat Rev Drug Discov, 1, 882-894.  
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.

 

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