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Molecular basis of DNA gating by topo IV and gyrase and its inhibition by antimicrobial drugs

拓扑IV和旋转酶DNA门控的分子基础及其抗菌药物的抑制作用

基本信息

批准号：
BB/K010069/1
负责人：
Larry Mark Fisher
金额：
$ 80.66万
依托单位：
St George's, University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FK010069%2F1
关键词：
Molecular basis DNA gating topo

项目摘要

Most life-forms whether humans, mammals, yeast or bacteria have a DNA genome. The DNA consists of two strands that wrap around each other to form the iconic DNA helix. During DNA replication, the helix must be unwound to allow copying and chromosome segregation. This process generates DNA supercoils and DNA tangles that can block replication. Topoisomerases solve the 'unwinding problem' by introducing transient single- or double-stranded breaks into DNA that dissipate supercoils and allow DNA synthesis to proceed. It is not surprising that topoisomerases are essential enzymes but they also turn out to be vital targets of antibacterial and anticancer drugs that inhibit cell growth. We aim to use biochemical and X-ray crystallographic approaches to study two bacterial topoisomerases called topo IV and gyrase. We wish to understand how these proteins act at the molecular level and how clinically important drugs such as fluoroquinolones target their functions. The work will focus on the well-characterised topo IV and gyrase from Streptococcus pneumoniae, a dangerous human pathogen that causes life-threatening pneumonia and meningitis. However the research has wider applications to other bacterial and microbial systems. Progress in this key area should aid development of new drugs that work against antibiotic-resistant organisms, a growing threat to our healthcare system.

大多数生命形式，无论是人类、哺乳动物、酵母还是细菌，都有一个DNA基因组。DNA由两条链组成，它们相互缠绕形成标志性的DNA螺旋。在DNA复制过程中，螺旋必须解开，以允许复制和染色体分离。这个过程会产生DNA超螺旋和DNA缠结，从而阻止复制。拓扑异构酶通过在DNA中引入瞬时的单链或双链断裂来消除超螺旋并允许DNA合成进行来解决“解旋问题”。拓扑异构酶是必需的酶，这并不奇怪，但它们也是抑制细胞生长的抗菌药物和抗癌药物的重要靶点。我们的目标是使用生物化学和X射线晶体学方法来研究两种称为topo IV和促旋酶的细菌拓扑异构酶。我们希望了解这些蛋白质如何在分子水平上发挥作用，以及临床上重要的药物如氟喹诺酮类药物如何靶向它们的功能。这项工作将集中在来自肺炎链球菌的具有良好特征的topo IV和促旋酶，肺炎链球菌是一种危险的人类病原体，可导致危及生命的肺炎和脑膜炎。然而，这项研究对其他细菌和微生物系统有更广泛的应用。这一关键领域的进展应该有助于开发对抗抗药性生物体的新药，这对我们的医疗保健系统构成了越来越大的威胁。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Trapping of the transport-segment DNA by the ATPase domains of a type II topoisomerase.

DOI：
10.1038/s41467-018-05005-x
发表时间：
2018-07-03
期刊：
Nature communications
影响因子：
16.6
作者：
Laponogov I;Pan XS;Veselkov DA;Skamrova GB;Umrekar TR;Fisher LM;Sanderson MR
通讯作者：
Sanderson MR

Structure of an 'open' clamp type II topoisomerase-DNA complex provides a mechanism for DNA capture and transport.

DOI：
10.1093/nar/gkt749
发表时间：
2013-11
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Laponogov I;Veselkov DA;Crevel IM;Pan XS;Fisher LM;Sanderson MR
通讯作者：
Sanderson MR

Exploring the active site of the Streptococcus pneumoniae topoisomerase IV-DNA cleavage complex with novel 7,8-bridged fluoroquinolones.

DOI：
10.1098/rsob.160157
发表时间：
2016-09
期刊：
Open biology
影响因子：
5.8
作者：
Laponogov I;Pan XS;Veselkov DA;Cirz RT;Wagman A;Moser HE;Fisher LM;Sanderson MR
通讯作者：
Sanderson MR

Functional determinants of gate-DNA selection and cleavage by bacterial type II topoisomerases.

DOI：
10.1093/nar/gkt696
发表时间：
2013-11
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Arnoldi E;Pan XS;Fisher LM
通讯作者：
Fisher LM

Structure of a quinolone-stabilized cleavage complex of topoisomerase IV from Klebsiella pneumoniae and comparison with a related Streptococcus pneumoniae complex.

DOI：
10.1107/s2059798316001212
发表时间：
2016-04
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
0
作者：
Veselkov DA;Laponogov I;Pan XS;Selvarajah J;Skamrova GB;Branstrom A;Narasimhan J;Prasad JV;Fisher LM;Sanderson MR
通讯作者：
Sanderson MR