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PDBsum entry 2hdr
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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
2hdr

 

 

 

 

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Contents
Protein chains
352 a.a. *
Ligands
PO4
4A3 ×15
Waters ×311
* Residue conservation analysis
PDB id:
2hdr
Name: Hydrolase
Title: Ampc beta-lactamase in complex with 4-amino-3-hydroxybenzoic acid
Structure: Beta-lactamase. Chain: a, b. Synonym: cephalosporinase. Engineered: yes
Source: Escherichia coli k12. Organism_taxid: 83333. Strain: k-12. Gene: ampc. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.20Å     R-factor:   0.197     R-free:   0.246
Authors: K.Babaoglu,B.K.Shoichet
Key ref:
K.Babaoglu and B.K.Shoichet (2006). Deconstructing fragment-based inhibitor discovery. Nat Chem Biol, 2, 720-723. PubMed id: 17072304 DOI: 10.1038/nchembio831
Date:
20-Jun-06     Release date:   07-Nov-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00811  (AMPC_ECOLI) -  Beta-lactamase from Escherichia coli (strain K12)
Seq:
Struc: 		377 a.a.
352 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: 10.1038/nchembio831 Nat Chem Biol 2:720-723 (2006)
PubMed id: 17072304  
 
 
Deconstructing fragment-based inhibitor discovery.
K.Babaoglu, B.K.Shoichet.
 
  ABSTRACT  
 
Fragment-based screens test multiple low-molecular weight molecules for binding to a target. Fragments often bind with low affinities but typically have better ligand efficiencies (DeltaG(bind)/heavy atom count) than traditional screening hits. This efficiency, combined with accompanying atomic-resolution structures, has made fragments popular starting points for drug discovery programs. Fragment-based design adopts a constructive strategy: affinity is enhanced either by cycles of functional-group addition or by joining two independent fragments together. The final inhibitor is expected to adopt the same geometry as the original fragment hit. Here we consider whether the inverse, deconstructive logic also applies--can one always parse a higher-affinity inhibitor into fragments that recapitulate the binding geometry of the larger molecule? Cocrystal structures of fragments deconstructed from a known beta-lactamase inhibitor suggest that this is not always the case.
 
  Selected figure(s)  
 
Figure 3.
Interacting side chains and active site Ser64 are shown as sticks to orient the viewer. The unbiased F[o] – F[c] electron density is also shown, contoured at 3 . 		Figure 4.
Shown is crystal structure of fragment F4 (purple carbons) overlaid on that of the lead L1 (white carbons).
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2006, 2, 720-723) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20191319 Y.Huang, and A.Dömling (2011).
The Gewald multicomponent reaction.
  Mol Divers, 15, 3.  
19151741 B.B.Yan, M.Z.Xue, B.Xiong, K.Liu, D.Y.Hu, and J.K.Shen (2009).
ScafBank: a public comprehensive Scaffold database to support molecular hopping.
  Acta Pharmacol Sin, 30, 251-258.  
19527033 C.P.Mpamhanga, D.Spinks, L.B.Tulloch, E.J.Shanks, D.A.Robinson, I.T.Collie, A.H.Fairlamb, P.G.Wyatt, J.A.Frearson, W.N.Hunter, I.H.Gilbert, and R.Brenk (2009).
One scaffold, three binding modes: novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening.
  J Med Chem, 52, 4454-4465.
PDB codes: 2wd7 2wd8 3gn1 3gn2
19416920 D.G.Teotico, K.Babaoglu, G.J.Rocklin, R.S.Ferreira, A.M.Giannetti, and B.K.Shoichet (2009).
Docking for fragment inhibitors of AmpC beta-lactamase.
  Proc Natl Acad Sci U S A, 106, 7455-7460.
PDB codes: 3gqz 3gr2 3grj 3gsg 3gtc 3gv9 3gvb
19443265 G.E.de Kloe, D.Bailey, R.Leurs, and I.J.de Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
19396178 S.Chung, J.B.Parker, M.Bianchet, L.M.Amzel, and J.T.Stivers (2009).
Impact of linker strain and flexibility in the design of a fragment-based inhibitor.
  Nat Chem Biol, 5, 407-413.
PDB codes: 3fcf 3fci 3fck 3fcl
18588493 C.D.Snow (2008).
Hunting for predictive computational drug-discovery models.
  Expert Rev Anti Infect Ther, 6, 291-293.  
18328272 G.M.Rishton (2008).
Molecular diversity in the context of leadlikeness: compound properties that enable effective biochemical screening.
  Curr Opin Chem Biol, 12, 340-351.  
18826206 H.A.Carlson, R.D.Smith, N.A.Khazanov, P.D.Kirchhoff, J.B.Dunbar, and M.L.Benson (2008).
Differences between high- and low-affinity complexes of enzymes and nonenzymes.
  J Med Chem, 51, 6432-6441.  
18321097 H.Ji, B.Z.Stanton, J.Igarashi, H.Li, P.Martásek, L.J.Roman, T.L.Poulos, and R.B.Silverman (2008).
Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors.
  J Am Chem Soc, 130, 3900-3914.
PDB codes: 3b3m 3b3n
18333608 K.Babaoglu, A.Simeonov, J.J.Irwin, M.E.Nelson, B.Feng, C.J.Thomas, L.Cancian, M.P.Costi, D.A.Maltby, A.Jadhav, J.Inglese, C.P.Austin, and B.K.Shoichet (2008).
Comprehensive mechanistic analysis of hits from high-throughput and docking screens against beta-lactamase.
  J Med Chem, 51, 2502-2511.
PDB codes: 2pu2 2pu4 2r9w 2r9x
18384152 P.Kolb, C.B.Kipouros, D.Huang, and A.Caflisch (2008).
Structure-based tailoring of compound libraries for high-throughput screening: discovery of novel EphB4 kinase inhibitors.
  Proteins, 73, 11-18.  
18061882 G.Siegal, E.Ab, and J.Schultz (2007).
Integration of fragment screening and library design.
  Drug Discov Today, 12, 1032-1039.  
17851109 H.Jhoti, A.Cleasby, M.Verdonk, and G.Williams (2007).
Fragment-based screening using X-ray crystallography and NMR spectroscopy.
  Curr Opin Chem Biol, 11, 485-493.  
17512966 M.F.Rega, M.Leone, D.Jung, N.J.Cotton, J.L.Stebbins, and M.Pellecchia (2007).
Structure-based discovery of a new class of Bcl-xL antagonists.
  Bioorg Chem, 35, 344-353.  
17108979 P.J.Hajduk (2006).
Puzzling through fragment-based drug design.
  Nat Chem Biol, 2, 658-659.  
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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