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Elife. 2018 Nov 27;7. pii: e41604. doi: 10.7554/eLife.41604.

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

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Life Sciences Institute, University of Michigan, Ann Arbor, United States.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States.
Department of Pharmaceutical Sciences and Biointerfaces Institute, University of Michigan, Ann Arbor, United States.
Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States.
Department of Biological Sciences, Purdue University, Indiana, United States.


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.


HDL metabolism; LCAT; biochemistry; chemical biology; cholesterol; high density lipoprotein; lecithin cholesterol acyltransferase; molecular biophysics; none; structural biology

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