PDBsum entry: 3jzf

Ligase

PDB id: 3jzf

Contents

Protein chains

380 a.a. *

447 a.a. *

Ligands

CO3

JZK

Waters ×543

* Residue conservation analysis

PDB id:

3jzf

Name:

Ligase

Title:

Crystal structure of biotin carboxylase from e. Coli in complex with benzimidazoles series

Structure:

Biotin carboxylase. Chain: a, b. Synonym: acetyl-coa carboxylase subunit a, acc. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 83333. Strain: k12. Gene: accc, fabg, b3256, jw3224. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.13Å R-factor: 0.203 R-free: 0.236

Authors:

P.Orth

Key ref:

C.C.Cheng et al. (2009). Discovery and optimization of antibacterial AccC inhibitors. Bioorg Med Chem Lett, 19, 6507-6514. PubMed id: 19875284 DOI: 10.1016/j.bmcl.2009.10.057

Date:

23-Sep-09 Release date: 03-Nov-09

Protein chain

P24182  (ACCC_ECOLI) -  Biotin carboxylase

Seq: 449 a.a.

Struc: 380 a.a.

Protein chain

P24182  (ACCC_ECOLI) -  Biotin carboxylase

Seq: 449 a.a.

Struc: 447 a.a.

Enzyme reactions

• Enzyme class 1: Chains A, B: E.C.6.3.4.14 - Biotin carboxylase.
• Reaction: ATP + biotin-[carboxyl-carrier-protein] + CO₂ = ADP + phosphate + carboxy-biotin-[carboxyl-carrier-protein]

ATP + biotin-[carboxyl-carrier-protein] + CO(2) (Bound ligand (Het Group name = CO3) matches with 75.00% similarity) = ADP + phosphate + carboxy-biotin-[carboxyl-carrier-protein]

• Enzyme class 2: Chains A, B: E.C.6.4.1.2 - Acetyl-CoA carboxylase.
• Reaction: ATP + acetyl-CoA + HCO₃^- = ADP + phosphate + malonyl-CoA

ATP + acetyl-CoA + HCO(3)(-) (Bound ligand (Het Group name = CO3) corresponds exactly) = ADP + phosphate + malonyl-CoA

• 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

 Gene Ontology (GO) functional annotation 

• Biological process: metabolic process (4 terms)
• Biochemical function: catalytic activity (7 terms)

reference

DOI no: 10.1016/j.bmcl.2009.10.057

Bioorg Med Chem Lett 19:6507-6514 (2009)

PubMed id: 19875284

Discovery and optimization of antibacterial AccC inhibitors.

C.C.Cheng, G.W.Shipps, Z.Yang, B.Sun, N.Kawahata, K.A.Soucy, A.Soriano, P.Orth, L.Xiao, P.Mann, T.Black.

ABSTRACT

The biotin carboxylase (AccC) is part of the multi-component bacterial acetyl coenzyme-A carboxylase (ACCase) and is essential for pathogen survival. We describe herein the affinity optimization of an initial hit to give 2-(2-chlorobenzylamino)-1-(cyclohexylmethyl)-1H-benzo[d]imidazole-5-carboxamide (1), which was identified using our proprietary Automated Ligand Identification System (ALIS).(1) The X-ray co-crystal structure of 1 was solved and revealed several key interactions and opportunities for further optimization in the ATP site of AccC. Structure Based Drug Design (SBDD) and parallel synthetic approaches resulted in a novel series of AccC inhibitors, exemplified by (R)-2-(2-chlorobenzylamino)-1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazo[4,5-b]pyridine-5-carboxamide (40). This compound is a potent and selective inhibitor of bacterial AccC with an IC(50) of 20 nM and a MIC of 0.8 microg/mL against a sensitized strain of Escherichia coli (HS294 E. coli).