Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters
Sterol transport proteins (STPs) play a pivotal role in cholesterol homeostasis and therefore are essential for healthy human physiology. Despite recent advances in dissecting functions of STPs in the human cell, there is still a significant knowledge gap regarding their specific biological function...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002438 |
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| author | Laura Depta Hogan P. Bryce-Rogers Nienke J. Dekker Anna Wiehl Bønke Nicolò Camporese Mingxing Qian Yuanjian Xu Douglas F. Covey Luca Laraia |
| author_facet | Laura Depta Hogan P. Bryce-Rogers Nienke J. Dekker Anna Wiehl Bønke Nicolò Camporese Mingxing Qian Yuanjian Xu Douglas F. Covey Luca Laraia |
| author_sort | Laura Depta |
| collection | DOAJ |
| description | Sterol transport proteins (STPs) play a pivotal role in cholesterol homeostasis and therefore are essential for healthy human physiology. Despite recent advances in dissecting functions of STPs in the human cell, there is still a significant knowledge gap regarding their specific biological functions and a lack of suitable selective probes for their study. Here, we profile fluorescent steroid-based probes across ten STPs, uncovering substantial differences in their selectivity, aiding the retrospective and prospective interpretation of biological results generated with those probes. These results guided the establishment of an STP screening panel combining diverse biophysical assays, enabling the evaluation of 42 steroid-based natural products and derivatives. Combining this with a thorough structural analysis revealed the molecular basis for STP-specific selectivity profiles, leading to the uncovering of several new potent and selective Aster-B inhibitors and supporting the role of this protein in steroidogenesis. |
| format | Article |
| id | doaj-art-f146daf8989e464faa1c40b1de52f983 |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-f146daf8989e464faa1c40b1de52f9832025-01-31T05:09:58ZengElsevierJournal of Lipid Research0022-22752025-02-01662100738Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transportersLaura Depta0Hogan P. Bryce-Rogers1Nienke J. Dekker2Anna Wiehl Bønke3Nicolò Camporese4Mingxing Qian5Yuanjian Xu6Douglas F. Covey7Luca Laraia8Department of Chemistry, Technical University of Denmark, Kemitorvet 207, Kgs. Lyngby, DenmarkDepartment of Chemistry, Technical University of Denmark, Kemitorvet 207, Kgs. Lyngby, DenmarkDepartment of Chemistry, Technical University of Denmark, Kemitorvet 207, Kgs. Lyngby, DenmarkDepartment of Chemistry, Technical University of Denmark, Kemitorvet 207, Kgs. Lyngby, DenmarkDepartment of Chemistry, Technical University of Denmark, Kemitorvet 207, Kgs. Lyngby, DenmarkDepartment of Developmental Biology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USADepartment of Developmental Biology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USADepartment of Developmental Biology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USADepartment of Chemistry, Technical University of Denmark, Kemitorvet 207, Kgs. Lyngby, Denmark; For correspondence: Luca LaraiaSterol transport proteins (STPs) play a pivotal role in cholesterol homeostasis and therefore are essential for healthy human physiology. Despite recent advances in dissecting functions of STPs in the human cell, there is still a significant knowledge gap regarding their specific biological functions and a lack of suitable selective probes for their study. Here, we profile fluorescent steroid-based probes across ten STPs, uncovering substantial differences in their selectivity, aiding the retrospective and prospective interpretation of biological results generated with those probes. These results guided the establishment of an STP screening panel combining diverse biophysical assays, enabling the evaluation of 42 steroid-based natural products and derivatives. Combining this with a thorough structural analysis revealed the molecular basis for STP-specific selectivity profiles, leading to the uncovering of several new potent and selective Aster-B inhibitors and supporting the role of this protein in steroidogenesis.http://www.sciencedirect.com/science/article/pii/S0022227524002438sterol transport proteinsligand selectivitysmall moleculesnatural productsstructure activity relationship |
| spellingShingle | Laura Depta Hogan P. Bryce-Rogers Nienke J. Dekker Anna Wiehl Bønke Nicolò Camporese Mingxing Qian Yuanjian Xu Douglas F. Covey Luca Laraia Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters Journal of Lipid Research sterol transport proteins ligand selectivity small molecules natural products structure activity relationship |
| title | Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters |
| title_full | Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters |
| title_fullStr | Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters |
| title_full_unstemmed | Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters |
| title_short | Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters |
| title_sort | endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters |
| topic | sterol transport proteins ligand selectivity small molecules natural products structure activity relationship |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002438 |
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