Structural Insights into Transporter-Mediated Drug Resistance in Infectious Diseases.
Structural Insights into Transporter-Mediated Drug Resistance in Infectious Diseases.
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DOI：
10.1016/j.jmb.2021.167005
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发表时间：
2021-08-06
影响因子：
5.6
通讯作者：
Mancia F
中科院分区：
文献类型：
--
作者：
Kim J;Cater RJ;Choy BC;Mancia F
传染病对全球公共卫生构成重大威胁。病原体可以通过多种途径获得对抗感染剂的抗性，包括转运蛋白介导的外排。通常，多药转运蛋白具有宽敞的，动态的，化学可塑性的结合位点，以帮助识别和跨细胞膜运输化学多样性底物。在这里，我们讨论了最近的结构调查的多药转运蛋白参与耐药的感染性疾病，属于ATP结合盒（ABC）超家族，主要的促进剂超家族（MFS），药物/代谢物转运蛋白（DMT）超家族，多药和有毒化合物挤出（MATE）家族，小的多药耐药（SMR）家族，和耐药-增殖-分裂（RND）超家族。这些结构上的见解为理解和对抗多药耐药性提供了宝贵的信息。代表性的多药物转运蛋白结构及其细胞位置。来自DMT、MATE、SMR、MFS、ABC和RND（超级）家族的多药转运蛋白的代表性结构。左侧：PfCRT（PDB ID：6 UKJ）在引起疟疾的寄生虫恶性疟原虫的消化空泡膜中表达，在那里它介导4-氨基喹啉从它们的作用部位流出。右：包括PfMATE（ID：6 FHZ）、Gdx-Clo（PDB ID：6 WK 5）、MdfA（PDB ID：6 GV 1）、MacB（PDB ID：5 NIK）和AcrB（PDB ID：5 NG 5）的多药物转运蛋白显示在革兰氏阴性菌的内膜中，其中它们介导宽范围的细胞毒性化合物的流出（参见表1）。MacB和AcrB分别通过PAP MacA和AcrA与TolC形成三方复合物，以介导穿过周质和外膜的外排。此外，AcrAB-TolC三联复合物与内膜肽AcrZ（绿色）相互作用。内膜蛋白以带状表示，从N-（蓝色）到C-（红色）末端以彩虹色显示。MacA、AcrA和TolC分别为粉红色、鲑鱼色和金色。图灵感来自于Dijun等人，2018.
Infectious diseases present a major threat to public health globally. Pathogens can acquire resistance to anti-infectious agents via several means including transporter-mediated efflux. Typically, multidrug transporters feature spacious, dynamic, and chemically malleable binding sites to aid in the recognition and transport of chemically diverse substrates across cell membranes. Here, we discuss recent structural investigations of multidrug transporters involved in resistance to infectious diseases that belong to the ATP-binding cassette (ABC) superfamily, the major facilitator superfamily (MFS), the drug/metabolite transporter (DMT) superfamily, the multidrug and toxic compound extrusion (MATE) family, the small multidrug resistance (SMR) family, and the resistance-nodulation-division (RND) superfamily. These structural insights provide invaluable information for understanding and combatting multidrug resistance. Representative multidrug transporter structures and their cellular locations. Representative structures of multidrug transporters from the DMT, MATE, SMR, MFS, ABC, and RND (super)families. Left: PfCRT (PDB ID: 6UKJ) is expressed in the digestive vacuolar membrane of the malaria-causing parasite Plasmodium falciparum, where it mediates efflux of 4-aminoquinolines from their site of action. Right: Multidrug transporters including PfMATE (ID: 6FHZ), Gdx-Clo (PDB ID: 6WK5), MdfA (PDB ID: 6GV1), MacB (PDB ID: 5NIK), and AcrB (PDB ID: 5NG5) are shown in the inner membrane of Gram-negative bacteria where they mediate efflux of a broad range of cytotoxic compounds (see Table 1). MacB and AcrB form tripartite complexes with TolC via the PAPs MacA and AcrA, respectively, to mediate efflux across the periplasm and outer membrane. Additionally, the AcrAB-TolC tripartite complex interacts with the inner membrane peptide AcrZ (green). Inner membrane proteins are shown in ribbon representation and colored in rainbow from the N- (blue) to the C- (red) terminus. MacA, AcrA, and TolC are colored in pink, salmon, and gold, respectively. Figure inspired by Dijun et al., 2018.
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影响因子：
6.4
作者：
Dhingra SK;Redhi D;Combrinck JM;Yeo T;Okombo J;Henrich PP;Cowell AN;Gupta P;Stegman ML;Hoke JM;Cooper RA;Winzeler E;Mok S;Egan TJ;Fidock DA
通讯作者：
Fidock DA
影响因子：
15
作者：
Cho, Min-Kyu;Gayen, Anindita;Traaseth, Nathaniel J.
通讯作者：
Traaseth, Nathaniel J.
影响因子：
4.8
作者：
Doshi, Rupak;van Veen, Hendrik W.
通讯作者：
van Veen, Hendrik W.
DOI：
10.1126/science.1168750
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Aller SG;Yu J;Ward A;Weng Y;Chittaboina S;Zhuo R;Harrell PM;Trinh YT;Zhang Q;Urbatsch IL;Chang G
通讯作者：
Chang G
DOI：
10.1073/pnas.1211831109
发表时间：
2012-10-16
影响因子：
11.1
作者：
Brill, Shlomo;Falk, Ofir Sade;Schuldiner, Shimon
通讯作者：
Schuldiner, Shimon