Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol
Lecithin:cholesterol acyltransferase (LCAT) and LCAT-activating compounds are being investigated as treatments for coronary heart disease (CHD) and familial LCAT deficiency (FLD). Herein we report the crystal structure of human LCAT in complex with a potent piperidinylpyrazolopyridine activator and...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/41604 |
| _version_ | 1818024116963246080 |
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| author | Kelly A Manthei Shyh-Ming Yang Bolormaa Baljinnyam Louise Chang Alisa Glukhova Wenmin Yuan Lita A Freeman David J Maloney Anna Schwendeman Alan T Remaley Ajit Jadhav John JG Tesmer |
| author_facet | Kelly A Manthei Shyh-Ming Yang Bolormaa Baljinnyam Louise Chang Alisa Glukhova Wenmin Yuan Lita A Freeman David J Maloney Anna Schwendeman Alan T Remaley Ajit Jadhav John JG Tesmer |
| author_sort | Kelly A Manthei |
| collection | DOAJ |
| description | Lecithin:cholesterol acyltransferase (LCAT) and LCAT-activating compounds are being investigated as treatments for coronary heart disease (CHD) and familial LCAT deficiency (FLD). Herein we report the crystal structure of human LCAT in complex with a potent piperidinylpyrazolopyridine activator and an acyl intermediate-like inhibitor, revealing LCAT in an active conformation. Unlike other LCAT activators, the piperidinylpyrazolopyridine activator binds exclusively to the membrane-binding domain (MBD). Functional studies indicate that the compound does not modulate the affinity of LCAT for HDL, but instead stabilizes residues in the MBD and facilitates channeling of substrates into the active site. By demonstrating that these activators increase the activity of an FLD variant, we show that compounds targeting the MBD have therapeutic potential. Our data better define the substrate binding site of LCAT and pave the way for rational design of LCAT agonists and improved biotherapeutics for augmenting or restoring reverse cholesterol transport in CHD and FLD patients. |
| first_indexed | 2024-12-10T03:55:06Z |
| format | Article |
| id | doaj.art-e39ef85950bb4a8db30d83b97e4ee9fa |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T03:55:06Z |
| publishDate | 2018-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e39ef85950bb4a8db30d83b97e4ee9fa2022-12-22T02:03:09ZengeLife Sciences Publications LtdeLife2050-084X2018-11-01710.7554/eLife.41604Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterolKelly A Manthei0https://orcid.org/0000-0003-3874-8228Shyh-Ming Yang1https://orcid.org/0000-0003-1928-136XBolormaa Baljinnyam2Louise Chang3Alisa Glukhova4Wenmin Yuan5Lita A Freeman6David J Maloney7Anna Schwendeman8Alan T Remaley9Ajit Jadhav10https://orcid.org/0000-0001-7955-1451John JG Tesmer11https://orcid.org/0000-0003-1125-3727Life Sciences Institute, University of Michigan, Ann Arbor, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United StatesDepartment of Pharmaceutical Sciences and Biointerfaces Institute, University of Michigan, Ann Arbor, United StatesLipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United StatesDepartment of Pharmaceutical Sciences and Biointerfaces Institute, University of Michigan, Ann Arbor, United StatesLipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United StatesDepartment of Biological Sciences, Purdue University, Indiana, United StatesLecithin:cholesterol acyltransferase (LCAT) and LCAT-activating compounds are being investigated as treatments for coronary heart disease (CHD) and familial LCAT deficiency (FLD). Herein we report the crystal structure of human LCAT in complex with a potent piperidinylpyrazolopyridine activator and an acyl intermediate-like inhibitor, revealing LCAT in an active conformation. Unlike other LCAT activators, the piperidinylpyrazolopyridine activator binds exclusively to the membrane-binding domain (MBD). Functional studies indicate that the compound does not modulate the affinity of LCAT for HDL, but instead stabilizes residues in the MBD and facilitates channeling of substrates into the active site. By demonstrating that these activators increase the activity of an FLD variant, we show that compounds targeting the MBD have therapeutic potential. Our data better define the substrate binding site of LCAT and pave the way for rational design of LCAT agonists and improved biotherapeutics for augmenting or restoring reverse cholesterol transport in CHD and FLD patients.https://elifesciences.org/articles/41604LCATHDL metabolismhigh density lipoproteinlecithin cholesterol acyltransferasecholesterol |
| spellingShingle | Kelly A Manthei Shyh-Ming Yang Bolormaa Baljinnyam Louise Chang Alisa Glukhova Wenmin Yuan Lita A Freeman David J Maloney Anna Schwendeman Alan T Remaley Ajit Jadhav John JG Tesmer Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol eLife LCAT HDL metabolism high density lipoprotein lecithin cholesterol acyltransferase cholesterol |
| title | Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol |
| title_full | Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol |
| title_fullStr | Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol |
| title_full_unstemmed | Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol |
| title_short | Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol |
| title_sort | molecular basis for activation of lecithin cholesterol acyltransferase by a compound that increases hdl cholesterol |
| topic | LCAT HDL metabolism high density lipoprotein lecithin cholesterol acyltransferase cholesterol |
| url | https://elifesciences.org/articles/41604 |
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