3G30

CTX-M-9 class A beta-lactamase complexed with compound 3 (G30)

3G30 の概要

• エントリーDOI: 10.2210/pdb3g30/pdb
• 関連するPDBエントリー: 3G2Y 3G2Z 3G31 3G32 3G34 3G35
• 分子名称: Beta-lactamase CTX-M-9a, (1S,2R)-2-[(2,5-difluorophenyl)carbamoyl]cyclopropanecarboxylic acid (3 entities in total)
• 機能のキーワード: ctx-m, beta-lactamase, molecular docking, fragment, inhibitor, antibiotic resistance, hydrolase, plasmid, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28696.07

構造登録者

Chen, Y.,Shoichet, B.K. (登録日: 2009-02-01, 公開日: 2009-03-24, 最終更新日: 2023-09-06)

主引用文献

Chen, Y.,Shoichet, B.K.
Molecular docking and ligand specificity in fragment-based inhibitor discovery
Nat.Chem.Biol., 5:358-364, 2009

PubMed Abstract: Fragment screens have successfully identified new scaffolds in drug discovery, often with relatively high hit rates (5%) using small screening libraries (1,000-10,000 compounds). This raises two questions: would other noteworthy chemotypes be found were one to screen all commercially available fragments (>300,000), and does the success rate imply low specificity of fragments? We used molecular docking to screen large libraries of fragments against CTX-M beta-lactamase. We identified ten millimolar-range inhibitors from the 69 compounds tested. The docking poses corresponded closely to the crystallographic structures subsequently determined. Notably, these initial low-affinity hits showed little specificity between CTX-M and an unrelated beta-lactamase, AmpC, which is unusual among beta-lactamase inhibitors. This is consistent with the idea that the high hit rates among fragments correlate to a low initial specificity. As the inhibitors were progressed, both specificity and affinity rose together, yielding to our knowledge the first micromolar-range noncovalent inhibitors against a class A beta-lactamase.

PubMed: 19305397
DOI: 10.1038/nchembio.155

実験手法

X-RAY DIFFRACTION (1.8 Å)