PDBsum entry 1w2x

Transferase

PDB id: 1w2x

Contents

Protein chains

682 a.a. *

Ligands

RCP ×3

Waters ×379

* Residue conservation analysis

PDB id:

1w2x

Name:

Transferase

Title:

Crystal structure of the carboxyltransferase domain of acetyl- coenzyme a carboxylase in complex with cp-640186

Structure:

Acetyl-coa carboxylase. Chain: a, b, c. Fragment: carboxyltransferase domain, residues 1482-2195. Synonym: acc. Engineered: yes. Other_details: cp-640186

Source:

Saccharomyces cerevisiae. Organism_taxid: 4932. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PDB file)

Resolution:

2.80Å R-factor: 0.197 R-free: 0.234

Authors:

H.Zhang,B.Tweel,J.Li,L.Tong

Key ref:

H.Zhang et al. (2004). Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with CP-640186. Structure, 12, 1683-1691. PubMed id: 15341732 DOI: 10.1016/j.str.2004.07.009

Date:

09-Jul-04 Release date: 09-Sep-04

Protein chains

Q00955  (ACAC_YEAST) -  Acetyl-CoA carboxylase from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 2233 a.a.

Struc: 682 a.a.

Enzyme reactions

• Enzyme class 2: E.C.6.3.4.14 - biotin carboxylase.
• Reaction: N₆-biotinyl-L-lysyl-[protein] + hydrogencarbonate + ATP = N₆- carboxybiotinyl-L-lysyl-[protein] + ADP + phosphate + H⁺
• Enzyme class 3: E.C.6.4.1.2 - acetyl-CoA carboxylase.
• Reaction: hydrogencarbonate + acetyl-CoA + ATP = malonyl-CoA + ADP + phosphate + H⁺
• Cofactor: 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

reference

DOI no: 10.1016/j.str.2004.07.009

Structure 12:1683-1691 (2004)

PubMed id: 15341732

Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with CP-640186.

H.Zhang, B.Tweel, J.Li, L.Tong.

ABSTRACT

Acetyl-coenzyme A carboxylases (ACCs) are important targets for the development of therapeutic agents against obesity, diabetes, and other diseases. CP-640186 is a potent inhibitor of mammalian ACCs and can reduce body weight and improve insulin sensitivity in test animals. It is believed to target the carboxyltransferase (CT) domain of these enzymes. Here we report the crystal structure of the yeast CT domain in complex with CP-640186. The inhibitor is bound in the active site at the interface of a dimer of the CT domain. CP-640186 has tight interactions with the putative biotin binding site in the CT domain and demonstrates a distinct mode of inhibiting the CT activity as compared to the herbicides that inhibit plant ACCs. The affinity of inhibitors for the CT domain has been assessed using kinetic and fluorescence anisotropy binding studies. The structural information identifies three regions for drug binding in the active site of CT.

Selected figure(s)

Figure 4.
Figure 4. Three Distinct Binding Regions in the Active Site of CT(A) Molecular surface of the active site region of yeast CT. The CoA and CP-640186 molecules are shown in gray and gold, respectively. This panel was produced with Grasp (Nicholls et al., 1991).(B) Comparison of the binding modes of CP-640186 (in gold), haloxyfop (black), and CoA (gray). This panel was produced with Ribbons (Carson, 1987).

The above figure is reprinted by permission from Cell Press: Structure (2004, 12, 1683-1691) copyright 2004.

Figure was selected by an automated process.