9SGR

S315N KatG mutant no heme

9SGR の概要

• エントリーDOI: 10.2210/pdb9sgr/pdb
• 関連するPDBエントリー: 9SGL 9SGM 9SGN 9SGO 9SGP 9SGQ 9SGS 9SGT 9SGY
• EMDBエントリー: 54878
• 分子名称: Catalase-peroxidase (1 entity in total)
• 機能のキーワード: catalase, peoxidase, enzyme, heme, metal binding protein
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 168192.52

構造登録者

Chaplin, A.,Allport, T. (登録日: 2025-08-22, 公開日: 2026-01-14)

主引用文献

Allport, T.,Chaplin, A.K.
Uncovering the structural impact of KatG Ser315 mutations in Mycobacterium tuberculosis via cryo-EM.
Protein Sci., 35:e70409-e70409, 2026

PubMed Abstract: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is responsible for a global health burden affecting over a quarter of the world's population. The increasing prevalence of drug-resistant TB poses a significant threat to current treatment strategies. Isoniazid (INH) is a first-line prodrug used in TB therapy, which requires activation by the catalase-peroxidase enzyme KatG. Upon activation, INH inhibits InhA, thereby disrupting mycolic acid biosynthesis, a crucial process for maintaining Mtb's distinctive, lipid-rich cell wall. The most common naturally occurring resistance-associated mutation in KatG is S315T, though other variants at this position, such as S315G, S315N, S315I, and S315R, have also been reported. In this study, we employ cryo-electron microscopy (cryo-EM) to investigate the structural basis of INH resistance conferred by these KatG variants. We present high-resolution cryo-EM structures that reveal heterogeneity in heme loading among the mutants. Detailed structural analysis highlights alterations in the hydrogen-bonding network and substrate access channel unique to each variant, offering direct comparisons with the wild-type (WT) KatG protein. Our findings provide a molecular explanation for clinical INH resistance and lay the groundwork for the rational design of next-generation anti-TB therapeutics.

PubMed: 41432360
DOI: 10.1002/pro.70409

実験手法

ELECTRON MICROSCOPY (2.6 Å)