Crystal structures of multidrug efflux transporters from Burkholderia pseudomallei suggest details of transport mechanism.
Crystal structures of multidrug efflux transporters from Burkholderia pseudomallei suggest details of transport mechanism.
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DOI：
10.1073/pnas.2215072120
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发表时间：
2023-07-18
影响因子：
11.1
通讯作者：
Murakami, Satoshi
中科院分区：
文献类型：
--
作者：
Kato, Takaaki;Okada, Ui;Hung, Li-Wei;Yamashita, Eiki;Kim, Heung-Bok;Kim, Chang-Yub;Terwilliger, Thomas C.;Schweizer, Herbert P.;Murakami, Satoshi
我们目前的晶体结构的RND药物外排转运蛋白，BpeB和BpeF从类鼻疽伯克霍尔德氏菌。RND药物外排转运蛋白的分子机制被描述为递归的三步功能旋转机制，即“进入”、“结合”和“挤出”。BpeB结构可以表示从挤出返回到访问状态的中间状态。我们还观察到一个底物结合位点。比较BpeB/F结构及其同源结构，我们提出了一个详细的底物结合和转运机制的RND转运蛋白。对这种机制的进一步了解可以发现具有减轻外排责任的新型抗生素，并开发特异性抑制剂来对抗包括伯克霍尔德氏菌在内的致病菌。BpeB和BpeF是来自类鼻疽伯克霍尔德氏菌的多药外排转运蛋白，其能够产生多药耐药性。在这里，我们报告的BpeB和BpeF的晶体结构，分别在2.94纳米和3.0纳米分辨率。BpeB被发现作为一个不对称的三聚体，与广泛接受的功能旋转机制，这种类型的转运。其中一个单体具有独特的结构，我们将其解释为沿着该功能循环的中间体。此外，结合在以前未描述的结合位点的去污剂分子提供了通过该途径的底物易位的见解。BpeF与来自肺炎克雷伯氏菌的OqxB的晶体结构具有结构相似性，其中两者都是由三个“结合”状态单体组成的对称三聚体。BpeB和BpeF的结构进一步加深了我们对属于HAE 1-RND超家族的转运蛋白的功能机制的理解。
We present the crystal structures of the RND drug efflux transporters, BpeB and BpeF from Burkholderia pseudomallei. The molecular mechanism of the RND drug efflux transporters by which the drugs are exported has been described as a recursive three-step functionally rotating mechanism, “access,” “binding,” and “extrusion.” The BpeB structure could represent an intermediate state that goes back from the extrusion to the access state. We also observed a substrate-binding site. Comparing BpeB/F structures and their homologous structures, we propose a detailed substrate binding and translocation mechanism of the RND transporters. Further understanding of this mechanism could enable the discovery of novel antibiotics with mitigated efflux liabilities and the development of specific inhibitors to combat pathogenic bacteria including Burkholderia. BpeB and BpeF are multidrug efflux transporters from Burkholderia pseudomallei that enable multidrug resistance. Here, we report the crystal structures of BpeB and BpeF at 2.94 Å and 3.0 Å resolution, respectively. BpeB was found as an asymmetric trimer, consistent with the widely-accepted functional rotation mechanism for this type of transporter. One of the monomers has a distinct structure that we interpret as an intermediate along this functional cycle. Additionally, a detergent molecule bound in a previously undescribed binding site provides insights into substrate translocation through the pathway. BpeF shares structural similarities with the crystal structure of OqxB from Klebsiella pneumoniae, where both are symmetric trimers composed of three “binding”-state monomers. The structures of BpeB and BpeF further our understanding of the functional mechanisms of transporters belonging to the HAE1-RND superfamily.
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影响因子：
16.6
作者：
Bharatham N;Bhowmik P;Aoki M;Okada U;Sharma S;Yamashita E;Shanbhag AP;Rajagopal S;Thomas T;Sarma M;Narjari R;Nagaraj S;Ramachandran V;Katagihallimath N;Datta S;Murakami S
通讯作者：
Murakami S
影响因子：
7.7
作者：
Matsunaga Y;Yamane T;Terada T;Moritsugu K;Fujisaki H;Murakami S;Ikeguchi M;Kidera A
通讯作者：
Kidera A
DOI：
10.3390/v13071331
发表时间：
2021-07-09
期刊：
Viruses
影响因子：
--
作者：
Lauman P;Dennis JJ
通讯作者：
Dennis JJ
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：
4.4
作者：
Hall, Carina M.;Baker, Anthony L.;Wagner, David M.
通讯作者：
Wagner, David M.