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.
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.
Reviewing Editor
- Arun Radhakrishnan, University of Texas Southwestern Medical Center, United States
Publication history
- Received: September 1, 2018
- Accepted: November 6, 2018
- Accepted Manuscript published: November 27, 2018 (version 1)
- Version of Record published: December 3, 2018 (version 2)
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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