Modeling the structural origins of drug resistance to isoniazid via key mutations in Mycobacterium tuberculosis catalase-peroxidase, KatG.
Modeling the structural origins of drug resistance to isoniazid via key mutations in Mycobacterium tuberculosis catalase-peroxidase, KatG.
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DOI：
10.1016/j.tube.2017.11.007
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Valafar F
中科院分区：
文献类型：
--
作者：
Marney MW;Metzger RP;Hecht D;Valafar F
他报告了2015年的104万例新结核病（TB）和180万个死亡，使结核病成为最成功的人类病原体，在感染性疾病中死亡率最高。证明了这一点这14个可以在Smegmatis中引起INH抗性。这些KATG的三级结构的突变，重点是蛋白质结构中的三个通道的变化。
WHO reported 10.4 million new tuberculosis (TB) cases and 1.8 million deaths in 2015, making M. tuberculosis the most successful human pathogen with highest mortality among infectious diseases. Drug-resistant TB is a major threat to global TB control. Recently Torres et al. identified 14 novel substitutions in M. tuberculosis-KatG (the enzyme associated with resistance to isoniazid—an important first-line anti-TB drug) and demonstrated that 12 of the 14 can cause INH-resistance in M. smegmatis. This study presents an in silico structure-based analysis of these 14 amino acid substitutions using homology models and x-ray crystal structures (when available) in M. tuberculosis. Our models demonstrate that several of these mutations cluster around three openings in the KatG tertiary structure which appear to initiate channels to the heme group at the catalytic center of the enzyme. We studied the effects of these mutations on the tertiary structure of KatG, focusing on conformational changes in the three channels in the protein structure. Our results suggest that the 14 novel mutations sufficiently restrict one or more of these access channels, thus potentially preventing INH from reaching the catalytic heme. These observations provide valuable insights into the structure-based origins of INH resistance and provide testable hypotheses for future experimental studies.
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DOI：
10.1039/c3cc47022a
发表时间：
2013-12-25
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Zhao X;Hersleth HP;Zhu J;Andersson KK;Magliozzo RS
通讯作者：
Magliozzo RS
影响因子：
4.9
作者：
Hazbon, Manzour Hernando;Brimacombe, Michael;Alland, David
通讯作者：
Alland, David
影响因子：
4.9
作者：
Timmins, GS;Master, S;Deretic, V
通讯作者：
Deretic, V
DOI：
10.1038/nsb834
发表时间：
2002-09-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Yamada, Y;Fujiwara, T;Tanaka, N
通讯作者：
Tanaka, N
影响因子：
13.2
作者：
Torres JN;Paul LV;Rodwell TC;Victor TC;Amallraja AM;Elghraoui A;Goodmanson AP;Ramirez-Busby SM;Chawla A;Zadorozhny V;Streicher EM;Sirgel FA;Catanzaro D;Rodrigues C;Gler MT;Crudu V;Catanzaro A;Valafar F
通讯作者：
Valafar F