3GSG

AmpC beta-lactamase in complex with Fragment-based Inhibitor

3GSG の概要

• エントリーDOI: 10.2210/pdb3gsg/pdb
• 関連するPDBエントリー: 3GQZ 3GR2 3GRJ 3GTC 3GV9 3GVB
• 分子名称: Beta-lactamase, PHOSPHATE ION, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: hydrolase, antibiotic resistance, periplasm, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Escherichia coli
• 細胞内の位置: Periplasm: P00811
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 80909.39

構造登録者

Teotico, D.T.,Shoichet, B.K. (登録日: 2009-03-26, 公開日: 2009-04-14, 最終更新日: 2023-09-06)

主引用文献

Teotico, D.G.,Babaoglu, K.,Rocklin, G.J.,Ferreira, R.S.,Giannetti, A.M.,Shoichet, B.K.
Docking for fragment inhibitors of AmpC beta-lactamase
Proc.Natl.Acad.Sci.USA, 106:7455-7460, 2009

PubMed Abstract: Fragment screens for new ligands have had wide success, notwithstanding their constraint to libraries of 1,000-10,000 molecules. Larger libraries would be addressable were molecular docking reliable for fragment screens, but this has not been widely accepted. To investigate docking's ability to prioritize fragments, a library of >137,000 such molecules were docked against the structure of beta-lactamase. Forty-eight fragments highly ranked by docking were acquired and tested; 23 had K(i) values ranging from 0.7 to 9.2 mM. X-ray crystal structures of the enzyme-bound complexes were determined for 8 of the fragments. For 4, the correspondence between the predicted and experimental structures was high (RMSD between 1.2 and 1.4 A), whereas for another 2, the fidelity was lower but retained most key interactions (RMSD 2.4-2.6 A). Two of the 8 fragments adopted very different poses in the active site owing to enzyme conformational changes. The 48% hit rate of the fragment docking compares very favorably with "lead-like" docking and high-throughput screening against the same enzyme. To understand this, we investigated the occurrence of the fragment scaffolds among larger, lead-like molecules. Approximately 1% of commercially available fragments contain these inhibitors whereas only 10(-7)% of lead-like molecules do. This suggests that many more chemotypes and combinations of chemotypes are present among fragments than are available among lead-like molecules, contributing to the higher hit rates. The ability of docking to prioritize these fragments suggests that the technique can be used to exploit the better chemotype coverage that exists at the fragment level.

PubMed: 19416920
DOI: 10.1073/pnas.0813029106

実験手法

X-RAY DIFFRACTION (2.1 Å)