دورية أكاديمية
Cholesterol Allosterically Modulates the Structure and Dynamics of the Taurocholate Export Pump (ABCB11).
| العنوان: | Cholesterol Allosterically Modulates the Structure and Dynamics of the Taurocholate Export Pump (ABCB11). |
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| المؤلفون: | Hosamani S; Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India., Chakraborty S; Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India. |
| المصدر: | The journal of physical chemistry letters [J Phys Chem Lett] 2024 Aug 08; Vol. 15 (31), pp. 7901-7908. Date of Electronic Publication: 2024 Jul 26. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101526034 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1948-7185 (Electronic) Linking ISSN: 19487185 NLM ISO Abbreviation: J Phys Chem Lett Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society |
| مواضيع طبية MeSH: | ATP Binding Cassette Transporter, Subfamily B, Member 11*/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 11*/chemistry , Cholesterol*/chemistry , Cholesterol*/metabolism , Taurocholic Acid*/chemistry , Taurocholic Acid*/metabolism, Humans ; Allosteric Regulation ; ATP-Binding Cassette Transporters/metabolism ; ATP-Binding Cassette Transporters/chemistry ; Binding Sites ; Molecular Dynamics Simulation ; Thermodynamics |
| مستخلص: | 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. |
| المشرفين على المادة: | 0 (ABCB11 protein, human) 0 (ATP Binding Cassette Transporter, Subfamily B, Member 11) 0 (ATP-Binding Cassette Transporters) 97C5T2UQ7J (Cholesterol) 5E090O0G3Z (Taurocholic Acid) |
| تواريخ الأحداث: | Date Created: 20240726 Date Completed: 20240808 Latest Revision: 20240820 |
| رمز التحديث: | 20240820 |
| DOI: | 10.1021/acs.jpclett.4c01341 |
| PMID: | 39058973 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1948-7185 |
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| DOI: | 10.1021/acs.jpclett.4c01341 |