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Title: Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol

Abstract

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.

Authors:
ORCiD logo [1]; ORCiD logo [2];  [2];  [1];  [1];  [3];  [4];  [2];  [3];  [4]; ORCiD logo [2]; ORCiD logo [5]
  1. Life Sciences Institute, University of Michigan, Ann Arbor, United States
  2. National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
  3. Department of Pharmaceutical Sciences and Biointerfaces Institute, University of Michigan, Ann Arbor, United States
  4. Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
  5. Department of Biological Sciences, Purdue University, Indiana, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
AHANIH
OSTI Identifier:
1493792
Resource Type:
Journal Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 7; Journal Issue: 11, 2018; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Manthei, Kelly A., Yang, Shyh-Ming, Baljinnyam, Bolormaa, Chang, Louise, Glukhova, Alisa, Yuan, Wenmin, Freeman, Lita A., Maloney, David J., Schwendeman, Anna, Remaley, Alan T., Jadhav, Ajit, and Tesmer, John JG. Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol. United States: N. p., 2018. Web. doi:10.7554/eLife.41604.
Manthei, Kelly A., Yang, Shyh-Ming, Baljinnyam, Bolormaa, Chang, Louise, Glukhova, Alisa, Yuan, Wenmin, Freeman, Lita A., Maloney, David J., Schwendeman, Anna, Remaley, Alan T., Jadhav, Ajit, & Tesmer, John JG. Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol. United States. doi:10.7554/eLife.41604.
Manthei, Kelly A., Yang, Shyh-Ming, Baljinnyam, Bolormaa, Chang, Louise, Glukhova, Alisa, Yuan, Wenmin, Freeman, Lita A., Maloney, David J., Schwendeman, Anna, Remaley, Alan T., Jadhav, Ajit, and Tesmer, John JG. Tue . "Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol". United States. doi:10.7554/eLife.41604.
@article{osti_1493792,
title = {Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol},
author = {Manthei, Kelly A. and Yang, Shyh-Ming and Baljinnyam, Bolormaa and Chang, Louise and Glukhova, Alisa and Yuan, Wenmin and Freeman, Lita A. and Maloney, David J. and Schwendeman, Anna and Remaley, Alan T. and Jadhav, Ajit and Tesmer, John JG},
abstractNote = {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.},
doi = {10.7554/eLife.41604},
journal = {eLife},
issn = {2050-084X},
number = 11, 2018,
volume = 7,
place = {United States},
year = {2018},
month = {11}
}