Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines.
Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines.
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DOI：
10.1038/s41467-020-20478-5
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发表时间：
2021-01-12
影响因子：
16.6
通讯作者：
Sharma A
中科院分区：
文献类型：
--
作者：
Sharma M;Malhotra N;Yogavel M;Harlos K;Melillo B;Comer E;Gonse A;Parvez S;Mitasev B;Fang FG;Schreiber SL;Sharma A
一系列新型双环氮杂环丁烷类化合物对疟原虫胞质苯丙氨酸tRNA合成酶（cFRS）的抑制作用已显示出在疟疾动物模型中预防疟疾传播、提供预防和提供单剂量治愈的潜力。然而，迄今为止，双环氮杂环丁烷抑制疟原虫cFRS的分子基础仍然未知。在这里，我们提出的结构和生物化学证据表明，双环氮杂环丁烷是竞争性抑制剂的L-苯丙氨酸，三个基板所需的cFRS催化的氨酰化反应，支持寄生虫中的蛋白质合成。重要的是，我们的PvcFRS-BRD 1389复合物的共晶体结构显示双环氮杂环丁烷配体结合到PvcFRS催化位点内的两个不同的亚位点。配体占据L-Phe位点沿着与辅助腔，并穿过ATP结合位点。鉴于BRD 1389识别残基在顶复门FRS中是保守的，这项工作为开发抗疟原虫和相关顶复门的药物奠定了结构框架。双环氮杂环丁烷抑制剂是靶向疟原虫胞质苯丙氨酸tRNA合成酶（cFRS）的有前途的抗疟药。在这里，Sharma等人使用PvcFRS与BRD 1389的共晶体结构提供了其机制的生物化学和结构基础。
The inhibition of Plasmodium cytosolic phenylalanine tRNA-synthetase (cFRS) by a novel series of bicyclic azetidines has shown the potential to prevent malaria transmission, provide prophylaxis, and offer single-dose cure in animal models of malaria. To date, however, the molecular basis of Plasmodium cFRS inhibition by bicyclic azetidines has remained unknown. Here, we present structural and biochemical evidence that bicyclic azetidines are competitive inhibitors of L-Phe, one of three substrates required for the cFRS-catalyzed aminoacylation reaction that underpins protein synthesis in the parasite. Critically, our co-crystal structure of a PvcFRS-BRD1389 complex shows that the bicyclic azetidine ligand binds to two distinct sub-sites within the PvcFRS catalytic site. The ligand occupies the L-Phe site along with an auxiliary cavity and traverses past the ATP binding site. Given that BRD1389 recognition residues are conserved amongst apicomplexan FRSs, this work lays a structural framework for the development of drugs against both Plasmodium and related apicomplexans. Bicyclic azetidine inhibitors are promising antimalarials that target the Plasmodium cytosolic phenylalanine tRNAsynthetase (cFRS). Here, Sharma et al. provide the biochemical and structural basis of its mechanism using co-crystal structure of PvcFRS with BRD1389.
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影响因子：
64.8
作者：
Kato N;Comer E;Sakata-Kato T;Sharma A;Sharma M;Maetani M;Bastien J;Brancucci NM;Bittker JA;Corey V;Clarke D;Derbyshire ER;Dornan GL;Duffy S;Eckley S;Itoe MA;Koolen KM;Lewis TA;Lui PS;Lukens AK;Lund E;March S;Meibalan E;Meier BC;McPhail JA;Mitasev B;Moss EL;Sayes M;Van Gessel Y;Wawer MJ;Yoshinaga T;Zeeman AM;Avery VM;Bhatia SN;Burke JE;Catteruccia F;Clardy JC;Clemons PA;Dechering KJ;Duvall JR;Foley MA;Gusovsky F;Kocken CH;Marti M;Morningstar ML;Munoz B;Neafsey DE;Sharma A;Winzeler EA;Wirth DF;Scherer CA;Schreiber SL
通讯作者：
Schreiber SL
DOI：
10.1107/s0907444913015308
发表时间：
2013-07
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Winter G;Lobley CM;Prince SM
通讯作者：
Prince SM
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：
7.3
作者：
Das, Pronay;Babbar, Palak;Reddy, D. Srinivasa
通讯作者：
Reddy, D. Srinivasa
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH