PDBsum entry: 3jzi

Ligase

PDB-id: 3jzi

Contents

Description

Header details

Header records

References

PROCHECK

Protein chains

445 a.a. *

Ligands

JZL ×2

Waters ×400

* Residue conservation analysis

Tools

Clefts Calculation

PDB id:

3jzi

Name:

Ligase

Title:

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

UniProt:

Chains A, B: P24182 (ACCC_ECOLI)

Seq:

Struc:

Seq:

449 a.a.

Struc:

445 a.a.

Key:

PfamA domain

Secondary structure

Enzyme class 1:

E.C.6.3.4.14   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

ATP + biotin-carboxyl-carrier protein + CO₂ = ADP + phosphate + carboxybiotin-carboxyl-carrier protein (see diagram below)

Enzyme class 2:

E.C.6.4.1.2   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

ATP + acetyl-CoA + HCO₃^- = ADP + phosphate + malonyl-CoA (see diagram below)

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.

Resolution:

2.31Å

R-factor:

0.187

R-free:

0.223

Authors:

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

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

Related entries:

3jzf

Quick_links

Procheck

Clefts

Surface

Key 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).