4N99

E. coli sliding clamp in complex with 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid

4N99 の概要

• エントリーDOI: 10.2210/pdb4n99/pdb
• 関連するPDBエントリー: 4N94 4N95 4N96 4N97 4N98 4N9A
• 分子名称: DNA polymerase III subunit beta, 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• 機能のキーワード: poliii beta, sliding clamp, dnan, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Escherichia coli
• 細胞内の位置: Cytoplasm: P0A988
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85669.64

構造登録者

Yin, Z.,Oakley, A.J. (登録日: 2013-10-19, 公開日: 2013-11-06, 最終更新日: 2023-09-20)

主引用文献

Yin, Z.,Whittell, L.R.,Wang, Y.,Jergic, S.,Liu, M.,Harry, E.J.,Dixon, N.E.,Beck, J.L.,Kelso, M.J.,Oakley, A.J.
Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach.
J.Med.Chem., 57:2799-2806, 2014

PubMed Abstract: The bacterial sliding clamp (SC), also known as the DNA polymerase III β subunit, is an emerging antibacterial target that plays a central role in DNA replication, serving as a protein-protein interaction hub with a common binding pocket to recognize linear motifs in the partner proteins. Here, fragment-based screening using X-ray crystallography produced four hits bound in the linear-motif-binding pocket of the Escherichia coli SC. Compounds structurally related to the hits were identified that inhibited the E. coli SC and SC-mediated DNA replication in vitro. A tetrahydrocarbazole derivative emerged as a promising lead whose methyl and ethyl ester prodrug forms showed minimum inhibitory concentrations in the range of 21-43 μg/mL against representative Gram-negative and Gram-positive bacteria species. The work demonstrates the utility of a fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity.

PubMed: 24592885
DOI: 10.1021/jm500122r

実験手法

X-RAY DIFFRACTION (2.3 Å)