PDBsum entry: 2w6p

Ligase

PDB id: 2w6p

Contents

Protein chains

446 a.a. *

387 a.a. *

Ligands

OA4

Waters ×725

* Residue conservation analysis

PDB id:

2w6p

Name:

Ligase

Title:

Crystal structure of biotin carboxylase from e. Coli in complex with 5-methyl-6-phenyl-quinazoline-2,4-diamine

Structure:

Acetyl-coa carboxylase. Chain: a, b. Synonym: biotin carboxylase. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 562. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.85Å R-factor: 0.188 R-free: 0.216

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

Protein chain

P24182  (ACCC_ECOLI) -  Biotin carboxylase

Seq: 449 a.a.

Struc: 446 a.a.

Protein chain

P24182  (ACCC_ECOLI) -  Biotin carboxylase

Seq: 449 a.a.

Struc: 387 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]
• Enzyme class 2: Chains A, B: E.C.6.4.1.2 - Acetyl-CoA carboxylase.
• Reaction: ATP + acetyl-CoA + HCO₃^- = ADP + phosphate + malonyl-CoA
• Cofactor: Biotin

Biotin (Bound ligand (Het Group name = OA4) matches with 52.17% 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 

• Biological process: metabolic process (4 terms)
• Biochemical function: catalytic activity (6 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.