Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
J Phys Chem Lett. 2024 Aug 8;15(31):7901-7908. doi: 10.1021/acs.jpclett.4c01341. Epub 2024 Jul 26.
The BSEP/ABCB11 transmembrane protein translocates taurine- and glycine-conjugated bile salts across the hepatocyte bilayer driven by ATP-hydrolysis. Direct inhibition of BSEP/ABCB11 leads to idiosyncratic drug-induced liver injury. ABCB11 is localized within the cholesterol-enriched lipid raft, and membrane cholesterol depletion leads to impaired taurocholate transport. However, structural insight into the mechanism of the cholesterol-mediated regulation of ABCB11 activity remains elusive. We used extensive molecular dynamics simulation coupled with well-tempered metadynamics to elucidate the role of membrane cholesterol in the structure and dynamics of ABCB11. We identified specific high-residence binding sites for cholesterol within the transmembrane domain. The free-energy simulations have elucidated that the bound cholesterol stabilizes the "inward-open" conformation of the protein. Cholesterol-ABCB11 interactions trigger allosteric communications between the transmembrane and nucleotide-binding domains through the linker region. Cholesterol depletion destabilizes the allosteric network of the protein. As a result, it adopts a more collapsed form with a reduced volume of the taurocholate-binding pocket.
BSEP/ABCB11 跨膜蛋白在 ATP 水解的驱动下将牛磺酸和甘氨酸结合的胆汁盐转运穿过肝细胞双层。BSEP/ABCB11 的直接抑制导致特发性药物性肝损伤。ABCB11 定位于富含胆固醇的脂筏内，胆固醇耗尽会导致胆盐转运受损。然而，胆固醇介导的 ABCB11 活性调节机制的结构见解仍然难以捉摸。我们使用广泛的分子动力学模拟结合良好的回火分子动力学来阐明膜胆固醇在 ABCB11 结构和动力学中的作用。我们在跨膜域内鉴定了胆固醇的特定高保留结合位点。自由能模拟表明，结合的胆固醇稳定了蛋白质的“内向开放”构象。胆固醇-ABCB11 相互作用通过连接区域触发跨膜和核苷酸结合结构域之间的变构通讯。胆固醇耗尽会破坏蛋白质的变构网络。结果，它采用了一种更折叠的形式，胆盐结合口袋的体积减小。
