Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds.
Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds.
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DOI：
10.1038/s41467-020-20405-8
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发表时间：
2021-01-08
影响因子：
16.6
通讯作者：
Anderluh M
中科院分区：
文献类型：
--
作者：
Kolarič A;Germe T;Hrast M;Stevenson CEM;Lawson DM;Burton NP;Vörös J;Maxwell A;Minovski N;Anderluh M
新型细菌II型拓扑异构酶抑制剂（NBTI）通过DNA促旋酶稳定单链DNA切割断裂，但其确切的作用机制至今仍处于假设状态。我们设计了一个小的NBTI文库，其具有改进的DNA促旋酶结合部分，导致低纳摩尔抑制和非常有效的抗菌活性。它们稳定单链切割复合物，并且重要的是，我们已经获得了其中NBTI以单一构象结合回旋酶-DNA而没有明显的静态无序的晶体结构。这直接证明了先前假设的NBTI作用机制，并表明它们通过不对称嵌入稳定单链切割，并使易断裂的磷酸盐移位。该晶体结构表明氯与两个与乙酰基相关的Ala 68残基的骨架羰基形成卤键。据我们所知，这种所谓的对称分叉卤键至今尚未在生物系统中被发现。DNA促旋酶抑制剂稳定单链DNA切割断裂的机制一直是假设的。在这里，作者使用具有改进的结合的抑制剂库显示了该机制的实验证据，并采用晶体分析来显示分叉的卤素键合。
Novel bacterial type II topoisomerase inhibitors (NBTIs) stabilize single-strand DNA cleavage breaks by DNA gyrase but their exact mechanism of action has remained hypothetical until now. We have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase–DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. This crystal stucture shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now. The mechanism of DNA gyrase inhibitor stabilization of single-strand DNA cleavage breaks by DNA gyrase has been hypothetical. Here, the authors show experimental evidence of the mechanism using a library of inhibitors with improved binding and employ crystal analysis to show bifurcated halogen bonding.
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抗菌QPT-1，抗癌药物依托泊苷和莫西沙星抑制DNA循环酶的结构基础。
影响因子：
16.6
作者：
Chan PF;Srikannathasan V;Huang J;Cui H;Fosberry AP;Gu M;Hann MM;Hibbs M;Homes P;Ingraham K;Pizzollo J;Shen C;Shillings AJ;Spitzfaden CE;Tanner R;Theobald AJ;Stavenger RA;Bax BD;Gwynn MN
通讯作者：
Gwynn MN
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.2
作者：
Dumele, Oliver;Wu, Dino;Diederich, Francois
通讯作者：
Diederich, Francois
影响因子：
--
作者：
Katz, BA;Sprengeler, PA;Mackman, RL
通讯作者：
Mackman, RL
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC