5Z9L

Bacterial GyrB ATPase domain in complex with a chemical fragment

5Z9L の概要

• エントリーDOI: 10.2210/pdb5z9l/pdb
• 分子名称: DNA gyrase subunit B, PHOSPHATE ION, 2-fluoro-4-hydroxybenzonitrile, ... (5 entities in total)
• 機能のキーワード: dna topoisomerase, antibacterial, drug target, fragment-base lead discovery, isomerase
• 由来する生物種: Escherichia coli (strain K12)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 46198.20

構造登録者

Huang, X.,Zhou, H. (登録日: 2018-02-03, 公開日: 2018-12-12, 最終更新日: 2023-11-22)

主引用文献

Huang, X.,Guo, J.,Liu, Q.,Gu, Q.,Xu, J.,Zhou, H.
Identification of an auxiliary druggable pocket in the DNA gyrase ATPase domain using fragment probes
Medchemcomm, 9:1619-1629, 2018

PubMed Abstract: Discovery of new drug binding sites on well-established targets is of great interest as it facilitates the design of new mechanistic inhibitors to overcome the acquired drug resistance. Small chemical fragments can easily enter and bind to the cavities on the protein surface. Thus, they can be used to probe new druggable pockets in proteins. DNA gyrase plays indispensable roles in DNA replication, and both its GyrA and GyrB subunits are clinically validated antibacterial targets. New mechanistic GyrB inhibitors are urgently desired since the withdrawal of novobiocin from the market by the FDA due to its reduced efficiency and other reasons. Here, a fragment library was screened against the GyrB ATPase domain by combining affinity- and bioactivity-based approaches. The following X-ray crystallographic efforts were made to determine the cocrystal structures of GyrB with ten fragment hits, and three different binding modes were disclosed. Fortunately, a hydrophobic pocket which is previously unknown was identified by two fragments. Fragments that bind to this pocket were shown to inhibit the ATPase activity as well as the DNA topological transition activity of DNA gyrase . A set of fragment analogs were screened to explore the binding capacity of this pocket and identify the better starting fragments for lead development. Phylogenetic analysis revealed that this pocket is conserved in most Gram-negative and also many Gram-positive human pathogenic bacteria, implying a broad-spectrum antibacterial potential and a lower risk of mutation. Thus, the novel druggable pocket and the starting fragments provide a novel basis for designing new GyrB-targeting therapeutics.

PubMed: 30429968
DOI: 10.1039/c8md00148k

実験手法

X-RAY DIFFRACTION (1.6 Å)