2W6Q

Crystal structure of Biotin carboxylase from E. coli in complex with the triazine-2,4-diamine fragment

2W6Q の概要

• エントリーDOI: 10.2210/pdb2w6q/pdb
• 関連するPDBエントリー: 1BNC 1DV1 1DV2 1K69 2GPS 2GPW 2J9G 2V58 2V59 2V5A 2VR1 2W6M 2W6N 2W6O 2W6P 2W6Z 2W70 2W71 2W7C
• 分子名称: BIOTIN CARBOXYLASE, 6-(2-phenoxyethoxy)-1,3,5-triazine-2,4-diamine, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: ligase, atp-binding, fatty acid biosynthesis, nucleotide-binding, lipid synthesis, atp-grasp domain, fragment screening
• 由来する生物種: ESCHERICHIA COLI
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 99338.72

構造登録者

Mochalkin, I.,Miller, J.R. (登録日: 2008-12-18, 公開日: 2009-05-19, 最終更新日: 2023-12-13)

主引用文献

Mochalkin, I.,Miller, J.R.,Narasimhan, L.S.,Thanabal, V.,Erdman, P.,Cox, P.,Prasad, J.V.,Lightle, S.,Huband, M.,Stover, K.
Discovery of Antibacterial Biotin Carboxylase Inhibitors by Virtual Screening and Fragment-Based Approaches.
Acs Chem.Biol., 4:473-, 2009

PubMed 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.

PubMed: 19413326
DOI: 10.1021/CB9000102

実験手法

X-RAY DIFFRACTION (2.05 Å)