Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5.
Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5.
复制标题
DOI：
10.1038/s41467-021-25574-8
复制
发表时间：
2021-09-06
影响因子：
16.6
通讯作者：
Schmitt L
中科院分区：
文献类型：
--
作者：
Harris A;Wagner M;Du D;Raschka S;Nentwig LM;Gohlke H;Smits SHJ;Luisi BF;Schmitt L
Pdr5是广泛的ABC转运蛋白超家族的成员，是参与多效耐药的临床相关亚群的代表。Pdr5及其同源物通过核苷酸的不偶联水解驱动药物外排，使面包酵母和致病真菌等生物能够在化学上不同的抗真菌剂存在下存活。在这里，我们展示了Pdr5的分子结构，用单粒子冷冻电镜解决，揭示了atp驱动的构象周期的细节，它通过两亲通道机械地驱动药物易位，以及保守连接环内作为核苷酸传感器的夹紧开关。在整个循环过程中，一半的转运体几乎保持不变，而另一半的转运体则经历变化，这些变化通过域间界面传递，以支持泵送分子的蠕动运动。本文提出的外排模型合理化了Pdr5的多效性影响，为开发有效的抗真菌化合物开辟了新的途径。Pdr5是一种ABC转运蛋白，对致病性真菌具有多药耐药性。在这里，Pdr5的结构分析提供了对Pdr5结构域不对称运动和广泛化合物外排的转运机制的见解。
Pdr5, a member of the extensive ABC transporter superfamily, is representative of a clinically relevant subgroup involved in pleiotropic drug resistance. Pdr5 and its homologues drive drug efflux through uncoupled hydrolysis of nucleotides, enabling organisms such as baker’s yeast and pathogenic fungi to survive in the presence of chemically diverse antifungal agents. Here, we present the molecular structure of Pdr5 solved with single particle cryo-EM, revealing details of an ATP-driven conformational cycle, which mechanically drives drug translocation through an amphipathic channel, and a clamping switch within a conserved linker loop that acts as a nucleotide sensor. One half of the transporter remains nearly invariant throughout the cycle, while its partner undergoes changes that are transmitted across inter-domain interfaces to support a peristaltic motion of the pumped molecule. The efflux model proposed here rationalises the pleiotropic impact of Pdr5 and opens new avenues for the development of effective antifungal compounds. Pdr5 is an ABC transporter conferring multidrug resistance to pathogenic fungi. Here, structural analysis of Pdr5 provides insights into the transport mechanism featuring asymmetric movements of Pdr5 domain and enabling efflux of a broad spectrum of compounds.
登录
查看更多内容
影响因子：
3.6
作者：
Egner, R;Bauer, BE;Kuchler, K
通讯作者：
Kuchler, K
影响因子：
64.8
作者：
Bi Y;Mann E;Whitfield C;Zimmer J
通讯作者：
Zimmer J
影响因子：
6.4
作者：
Chen, Li;Hou, Wen-Tao;Chen, Yuxing
通讯作者：
Chen, Yuxing
DOI：
10.1073/pnas.96.12.7065
发表时间：
1999-06-08
影响因子：
11.1
作者：
Ahmadian, MR;Zor, T;Scheffzek, K
通讯作者：
Scheffzek, K
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