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PDBsum entry 2w6o

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protein ligands metals Protein-protein interface(s) links
Ligase PDB id
2w6o
Jmol
Contents
Protein chains
445 a.a. *
Ligands
OA3 ×2
Metals
_CL ×2
Waters ×128
* Residue conservation analysis
PDB id:
2w6o
Name: Ligase
Title: Crystal structure of biotin carboxylase from e. Coli in complex with 4-amino-7,7-dimethyl-7,8-dihydro- quinazolinone fragment
Structure: Biotin carboxylase. Chain: a, c. Synonym: acetyl-coa carboxylase subunit a, acc. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.50Å     R-factor:   0.234     R-free:   0.308
Authors: I.Mochalkin,J.R.Miller
Key ref: I.Mochalkin et al. (2009). Discovery of antibacterial biotin carboxylase inhibitors by virtual screening and fragment-based approaches. ACS Chem Biol, 4, 473-483. PubMed id: 19413326 DOI: 10.1021/cb9000102
Date:
18-Dec-08     Release date:   19-May-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P24182  (ACCC_ECOLI) -  Biotin carboxylase
Seq:
Struc:
449 a.a.
445 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: E.C.6.3.4.14  - Biotin carboxylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + biotin-[carboxyl-carrier-protein] + CO2 = ADP + phosphate + carboxy-biotin-[carboxyl-carrier-protein]
ATP
+ biotin-[carboxyl-carrier-protein]
+ CO(2)
= ADP
+ phosphate
+ carboxy-biotin-[carboxyl-carrier-protein]
   Enzyme class 2: E.C.6.4.1.2  - Acetyl-CoA carboxylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + acetyl-CoA + HCO3- = ADP + phosphate + malonyl-CoA
ATP
+ acetyl-CoA
+ HCO(3)(-)
= ADP
+ phosphate
+ malonyl-CoA
      Cofactor: Biotin
Biotin
Bound ligand (Het Group name = OA3) matches with 50.00% similarity
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     metabolic process   6 terms 
  Biochemical function     catalytic activity     8 terms  

 

 
    reference    
 
 
DOI no: 10.1021/cb9000102 ACS Chem Biol 4:473-483 (2009)
PubMed id: 19413326  
 
 
Discovery of antibacterial biotin carboxylase inhibitors by virtual screening and fragment-based approaches.
I.Mochalkin, J.R.Miller, L.Narasimhan, V.Thanabal, P.Erdman, P.B.Cox, J.V.Prasad, S.Lightle, M.D.Huband, C.K.Stover.
 
  ABSTRACT  
 
As part of our effort to inhibit bacterial fatty acid biosynthesis through the recently validated target biotin carboxylase, we employed a unique combination of two emergent lead discovery strategies. We used both de novo fragment-based drug discovery and virtual screening, which employs 3D shape and electrostatic property similarity searching. We screened a collection of unbiased low-molecular-weight molecules and identified a structurally diverse collection of weak-binding but ligand-efficient fragments as potential building blocks for biotin carboxylase ATP-competitive inhibitors. Through iterative cycles of structure-based drug design relying on successive fragment costructures, we improved the potency of the initial hits by up to 3000-fold while maintaining their ligand-efficiency and desirable physicochemical properties. In one example, hit-expansion efforts resulted in a series of amino-oxazoles with antibacterial activity. These results successfully demonstrate that virtual screening approaches can substantially augment fragment-based screening approaches to identify novel antibacterial agents.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21513713 A.Fabbretti, C.O.Gualerzi, and L.Brandi (2011).
How to cope with the quest for new antibiotics.
  FEBS Lett, 585, 1673-1681.  
21120858 B.R.Novak, D.Moldovan, G.L.Waldrop, and M.S.de Queiroz (2011).
Behavior of the ATP grasp domain of biotin carboxylase monomers and dimers studied using molecular dynamics simulations.
  Proteins, 79, 622-632.  
21277383 P.J.Edwards (2011).
The design and synthesis of libraries for the discovery of antibacterial and antifungal substances.
  Drug Discov Today, 16, 278-279.  
21097780 U.Pieper, B.M.Webb, D.T.Barkan, D.Schneidman-Duhovny, A.Schlessinger, H.Braberg, Z.Yang, E.C.Meng, E.F.Pettersen, C.C.Huang, R.S.Datta, P.Sampathkumar, M.S.Madhusudhan, K.Sjölander, T.E.Ferrin, S.K.Burley, and A.Sali (2011).
ModBase, a database of annotated comparative protein structure models, and associated resources.
  Nucleic Acids Res, 39, D465-D474.  
20223699 A.G.Coyne, D.E.Scott, and C.Abell (2010).
Drugging challenging targets using fragment-based approaches.
  Curr Opin Chem Biol, 14, 299-307.  
20471246 C.W.Murray, and T.L.Blundell (2010).
Structural biology in fragment-based drug design.
  Curr Opin Struct Biol, 20, 497-507.  
21058956 M.N.Gwynn, A.Portnoy, S.F.Rittenhouse, and D.J.Payne (2010).
Challenges of antibacterial discovery revisited.
  Ann N Y Acad Sci, 1213, 5.  
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.