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Ligase PDB id
1w93
Jmol
Contents
Protein chain
549 a.a. *
Waters ×149
* Residue conservation analysis
PDB id:
1w93
Name: Ligase
Title: Crystal structure of biotin carboxylase domain of acetyl- coenzyme a carboxylase from saccharomyces cerevisiae
Structure: Acetyl-coenzyme a carboxylase. Chain: a. Fragment: biotin carboxylase domain, residues 14-566. Synonym: acc. Engineered: yes
Source: Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.50Å     R-factor:   0.254     R-free:   0.323
Authors: Y.Shen,S.L.Volrath,S.C.Weatherly,T.D.Elich,L.Tong
Key ref:
Y.Shen et al. (2004). A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A carboxylase by soraphen A, a macrocyclic polyketide natural product. Mol Cell, 16, 881-891. PubMed id: 15610732 DOI: 10.1016/j.molcel.2004.11.034
Date:
05-Oct-04     Release date:   04-Jan-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q00955  (ACAC_YEAST) -  Acetyl-CoA carboxylase
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		2233 a.a.
549 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: 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 3: 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
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!
  Biological process     metabolic process   1 term 
  Biochemical function     catalytic activity     4 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.molcel.2004.11.034 Mol Cell 16:881-891 (2004)
PubMed id: 15610732  
 
 
A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A carboxylase by soraphen A, a macrocyclic polyketide natural product.
Y.Shen, S.L.Volrath, S.C.Weatherly, T.D.Elich, L.Tong.
 
  ABSTRACT  
 
Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism. Soraphen A, a macrocyclic polyketide natural product, is a nanomolar inhibitor against the biotin carboxylase (BC) domain of human, yeast, and other eukaryotic ACCs. Here we report the crystal structures of the yeast BC domain, alone and in complex with soraphen A. Soraphen has extensive interactions with an allosteric site, about 25 A from the active site. The specificity of soraphen is explained by large structural differences between the eukaryotic and prokaryotic BC in its binding site, confirmed by our studies on the effects of single-site mutations in this binding site. Unexpectedly, our structures suggest that soraphen may bind in the BC dimer interface and inhibit the BC activity by disrupting the oligomerization of this domain. Observations from native gel electrophoresis confirm this structural insight. The structural information provides a foundation for structure-based design of new inhibitors against these enzymes.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Structure of Biotin Carboxylase in Complex with Soraphen A(A) Chemical structure of soraphen A. The numbering scheme of atoms in the macrocycle is shown.(B) Final 2F[o] − F[c] electron density at 1.8 Å resolution for soraphen A, contoured at 1σ. Produced with Setor (Evans, 1993).(C) Schematic drawing of the structure of yeast BC domain in complex with soraphen A. Residues 535–538 (in the αR-αS loop) are disordered in this molecule and are shown in gray. Soraphen A is shown as a stick model in green for carbon atoms, labeled Sor. The expected position of ATP, as observed in the E. coli BC subunit (Thoden et al., 2000), is shown in gray.(D) Side view of the structure of the BC:soraphen complex. The different domains are colored differently. (C) and (D) were produced with Ribbons (Carson, 1987). 		Figure 3.
Figure 3. The Binding Mode of Soraphen A(A) Stereographic drawing showing the binding site for soraphen A. Produced with Ribbons (Carson, 1987).(B) Schematic drawing of the interactions between soraphen A and the BC domain.(C) Molecular surface of the BC domain in the soraphen binding site. Produced with Grasp (Nicholls et al., 1991).
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2004, 16, 881-891) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21283550 C.Tuzmen, and B.Erman (2011).
Identification of ligand binding sites of proteins using the gaussian network model.
  PLoS One, 6, e16474.  
21204864 G.Gago, L.Diacovich, A.Arabolaza, S.C.Tsai, and H.Gramajo (2011).
Fatty acid biosynthesis in actinomycetes.
  FEMS Microbiol Rev, 35, 475-497.  
20952656 C.L.Colbert, C.W.Kim, Y.A.Moon, L.Henry, M.Palnitkar, W.B.McKean, K.Fitzgerald, J.Deisenhofer, J.D.Horton, and H.J.Kwon (2010).
Crystal structure of Spot 14, a modulator of fatty acid synthesis.
  Proc Natl Acad Sci U S A, 107, 18820-18825.
PDB code: 3ont
20725044 C.S.Huang, K.Sadre-Bazzaz, Y.Shen, B.Deng, Z.H.Zhou, and L.Tong (2010).
Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase.
  Nature, 466, 1001-1005.
PDB code: 3n6r
20520915 K.J.Weissman, and R.Müller (2010).
Myxobacterial secondary metabolites: bioactivities and modes-of-action.
  Nat Prod Rep, 27, 1276-1295.  
19213731 C.Y.Chou, L.P.Yu, and L.Tong (2009).
Crystal structure of biotin carboxylase in complex with substrates and implications for its catalytic mechanism.
  J Biol Chem, 284, 11690-11697.
PDB codes: 3g8c 3g8d
19506028 S.A.McMahon, G.A.Roberts, K.A.Johnson, L.P.Cooper, H.Liu, J.H.White, L.G.Carter, B.Sanghvi, M.Oke, M.D.Walkinshaw, G.W.Blakely, J.H.Naismith, and D.T.Dryden (2009).
Extensive DNA mimicry by the ArdA anti-restriction protein and its role in the spread of antibiotic resistance.
  Nucleic Acids Res, 37, 4887-4897.
PDB code: 2w82
19362848 S.M.Firestine, H.Paritala, J.E.McDonnell, J.B.Thoden, and H.M.Holden (2009).
Identification of inhibitors of N5-carboxyaminoimidazole ribonucleotide synthetase by high-throughput screening.
  Bioorg Med Chem, 17, 3317-3323.  
18725455 I.Mochalkin, J.R.Miller, A.Evdokimov, S.Lightle, C.Yan, C.K.Stover, and G.L.Waldrop (2008).
Structural evidence for substrate-induced synergism and half-sites reactivity in biotin carboxylase.
  Protein Sci, 17, 1706-1718.
PDB codes: 2c00 2j9g 2vpq 2vqd 2vr1
17876819 Y.S.Cho, J.I.Lee, D.Shin, H.T.Kim, Y.H.Cheon, C.I.Seo, Y.E.Kim, Y.L.Hyun, Y.S.Lee, K.Sugiyama, S.Y.Park, S.Ro, J.M.Cho, T.G.Lee, and Y.S.Heo (2008).
Crystal structure of the biotin carboxylase domain of human acetyl-CoA carboxylase 2.
  Proteins, 70, 268-272.
PDB code: 2hjw
17642515 S.Kondo, Y.Nakajima, S.Sugio, S.Sueda, M.N.Islam, and H.Kondo (2007).
Structure of the biotin carboxylase domain of pyruvate carboxylase from Bacillus thermodenitrificans.
  Acta Crystallogr D Biol Crystallogr, 63, 885-890.
PDB code: 2dzd
16983687 L.Tong, and H.J.Harwood (2006).
Acetyl-coenzyme A carboxylases: versatile targets for drug discovery.
  J Cell Biochem, 99, 1476-1488.  
16793549 Y.Shen, C.Y.Chou, G.G.Chang, and L.Tong (2006).
Is dimerization required for the catalytic activity of bacterial biotin carboxylase?
  Mol Cell, 22, 807-818.
PDB codes: 2gps 2gpw
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.