结核分枝杆菌1-脱氧-d-木质素糖5-磷酸合成酶DXPS的载脂蛋白结构:动力学和抑制剂设计的意义。

IF 2.5 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemical and biophysical research communications Pub Date : 2025-02-02 DOI:10.1016/j.bbrc.2024.151246
Victor O. Gawriljuk , Alaa Alhayek , Anna K.H. Hirsch , Matthew R. Groves
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引用次数: 0

摘要

酶1-脱氧-d-木醛糖-5-磷酸合成酶(DXPS)催化MEP途径的第一步,这是细菌中不存在的类异戊二烯生物合成的关键过程,使其成为一个有希望的药物靶点。我们提出了结核分枝杆菌DXPS的载脂蛋白形式的结构,通过从预形成的晶体中去除二磷酸硫胺素(ThDP)和金属的浸泡方法获得。载脂蛋白结构在活性位点附近有三个没有电子密度的区域,这是载脂蛋白所特有的。与其他同源DXPS结构的比较突出了对辅因子缺失的相似动态响应。尽管灵活性增加了,但活性和ThDP结合的关键残基保留了它们的位置,保持了催化核心的结构完整性。这些发现证明了ThDP在维持DXPS稳定性方面的关键作用,并提示载脂蛋白状态的动态结构变化可能影响靶向辅助因子位点的抑制剂结合。
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Apo structure of Mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate synthase DXPS: Dynamics and implications for inhibitor design
The enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS) catalyses the first step of the MEP pathway, a key process for isoprenoid biosynthesis in bacteria that is absent in humans, making it a promising drug target. We present the structure of Mycobacterium tuberculosis DXPS in its apo form, obtained through a soaking method that removes thiamine diphosphate (ThDP) and metals from pre-formed crystals. The apo structure had three regions with absence of electron density near the active site that are unique to the apo form of the enzyme. Comparisons with other homologous DXPS structures highlight a similar dynamic response to cofactor absence. Despite the increased flexibility, key residues for the activity and ThDP binding retain their positions, preserving the structural integrity of the catalytic core. These findings demonstrate the critical role of ThDP in maintaining DXPS stability and suggest that dynamic structural changes in the apo state may influence inhibitor binding targeting the cofactor site.
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来源期刊
Biochemical and biophysical research communications
Biochemical and biophysical research communications 生物-生化与分子生物学
CiteScore
6.10
自引率
0.00%
发文量
1400
审稿时长
14 days
期刊介绍: Biochemical and Biophysical Research Communications is the premier international journal devoted to the very rapid dissemination of timely and significant experimental results in diverse fields of biological research. The development of the "Breakthroughs and Views" section brings the minireview format to the journal, and issues often contain collections of special interest manuscripts. BBRC is published weekly (52 issues/year).Research Areas now include: Biochemistry; biophysics; cell biology; developmental biology; immunology ; molecular biology; neurobiology; plant biology and proteomics
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