1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol

  1. Kelly A Manthei
  2. Shyh-Ming Yang
  3. Bolormaa Baljinnyam
  4. Louise Chang
  5. Alisa Glukhova
  6. Wenmin Yuan
  7. Lita A Freeman
  8. David J Maloney
  9. Anna Schwendeman
  10. Alan T Remaley
  11. Ajit Jadhav
  12. John JG Tesmer  Is a corresponding author
  1. University of Michigan, United States
  2. National Institutes of Health, United States
  3. National Heart, Lung, and Blood Institute, National Institutes of Health, United States
  4. Purdue University, United States
Research Article
  • Cited 13
  • Views 1,853
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Cite this article as: eLife 2018;7:e41604 doi: 10.7554/eLife.41604

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.

The following data sets were generated

Article and author information

Author details

  1. Kelly A Manthei

    Life Sciences Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3874-8228
  2. Shyh-Ming Yang

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1928-136X
  3. Bolormaa Baljinnyam

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Louise Chang

    Life Sciences Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Alisa Glukhova

    Life Sciences Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Wenmin Yuan

    Department of Pharmaceutical Science, Biointerfaces Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lita A Freeman

    Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. David J Maloney

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Anna Schwendeman

    Department of Pharmaceutical Science, Biointerfaces Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Alan T Remaley

    Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Ajit Jadhav

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7955-1451
  12. John JG Tesmer

    Department of Biological Sciences, Purdue University, West Lafayette, United States
    For correspondence
    jtesmer@purdue.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1125-3727

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

  1. Arun Radhakrishnan, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: September 1, 2018
  2. Accepted: November 6, 2018
  3. Accepted Manuscript published: November 27, 2018 (version 1)
  4. 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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