Structural basis for substrate and inhibitor recognition of human multidrug transporter MRP4.
Structural basis for substrate and inhibitor recognition of human multidrug transporter MRP4.
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DOI：
10.1038/s42003-023-04935-7
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发表时间：
2023-05-22
影响因子：
5.9
通讯作者：
Liu, Zhongmin
中科院分区：
文献类型：
--
作者：
Huang, Ying;Xue, Chenyang;Wang, Liangdong;Bu, Ruiqian;Mu, Jianqiang;Wang, Yong;Liu, Zhongmin
人多药耐药蛋白4（Human multidrug resistance protein 4，hMRP 4，也称为ABCC 4）具有MRP亚家族的代表性拓扑结构，跨膜转运各种底物并有助于多药耐药的发展。然而，由于缺乏高分辨率结构，hMRP 4的潜在转运机制仍不清楚。在这里，我们使用低温电子显微镜（cryo-EM），以解决其近原子结构的apo向内开放和ATP绑定向外开放的状态。我们还捕获了PGE 1底物结合的结构，重要的是，hMRP 4与舒林酸复合物的结合结构，揭示了底物和抑制剂竞争相同的疏水结合口袋，尽管具有不同的结合模式。此外，我们的cryo-EM结构，连同分子动力学模拟和生化分析，揭示了底物转运和抑制机制的结构基础，对hMRP 4靶向药物的开发具有重要意义。冷冻电镜结构，MD模拟，和人多药耐药相关蛋白4在载脂蛋白向内开放，ATP结合向外开放，前列腺素E1底物结合，舒林酸底物结合状态的生化分析提供了底物转运和抑制机制的见解。
Human multidrug resistance protein 4 (hMRP4, also known as ABCC4), with a representative topology of the MRP subfamily, translocates various substrates across the membrane and contributes to the development of multidrug resistance. However, the underlying transport mechanism of hMRP4 remains unclear due to a lack of high-resolution structures. Here, we use cryogenic electron microscopy (cryo-EM) to resolve its near-atomic structures in the apo inward-open and the ATP-bound outward-open states. We also capture the PGE1 substrate-bound structure and, importantly, the inhibitor-bound structure of hMRP4 in complex with sulindac, revealing that substrate and inhibitor compete for the same hydrophobic binding pocket although with different binding modes. Moreover, our cryo-EM structures, together with molecular dynamics simulations and biochemical assay, shed light on the structural basis of the substrate transport and inhibition mechanism, with implications for the development of hMRP4-targeted drugs. Cryo-EM structures, MD simulations, and biochemical assays of human multidrug resistance-associated protein 4 in apo inward-open, ATP-bound outward-open, PGE1 substrate-bound, and sulindac inhibitor-bound states provide insights into substrate transport and inhibition mechanism.
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DOI：
10.1124/jpet.106.110379
发表时间：
2007-01-01
影响因子：
3.5
作者：
El-Sheikh, Azza A. K.;van den Heuvel, Jeroen J. M. W.;Russel, Frans G. M.
通讯作者：
Russel, Frans G. M.
影响因子：
10.1
作者：
Wolf R;Grammbauer S;Palankar R;Tolksdorf C;Moritz E;Böhm A;Hasan M;Hafkemeyer A;Greinacher A;Tzvetkov MV;Rauch BH;Jedlitschky G
通讯作者：
Jedlitschky G
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
DOI：
10.1165/rcmb.2013-0156oc
发表时间：
2013-10-01
影响因子：
6.4
作者：
Conner, Gregory E.;Ivonnet, Pedro;Salathe, Matthias
通讯作者：
Salathe, Matthias
DOI：
10.1016/0161-4630(81)90044-6
发表时间：
1981-01-01
期刊：
PROSTAGLANDINS AND MEDICINE
影响因子：
--
作者：
LIPPTON, HL;KADOWITZ, PJ
通讯作者：
KADOWITZ, PJ