Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol
- University of Michigan, United States
- National Institutes of Health, United States
- National Heart, Lung, and Blood Institute, National Institutes of Health, United States
- Purdue University, United States
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.
Data availability
The atomic coordinates and structure factors for the complex have been deposited in the PDB with accession code 6MVD.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute
- Alan T Remaley
National Center for Advancing Translational Sciences (Division of Preclinical Innovation)
- Ajit Jadhav
American Heart Association (15POST24870001)
- Kelly A Manthei
National Institutes of Health (F32HL131288)
- Kelly A Manthei
American Heart Association (16POST27760002)
- Wenmin Yuan
National Institutes of Health (HL071818)
- John JG Tesmer
National Institutes of Health (HL122416)
- John JG Tesmer
American Heart Association (13SDG17230049)
- Anna Schwendeman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol
eLife 7:e41604.
https://doi.org/10.7554/eLife.41604
