Journal article

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

Kelly A Manthei, Shyh-Ming Yang, Bolormaa Baljinnyam, Louise Chang, Alisa Glukhova, Wenmin Yuan, Lita A Freeman, David J Maloney, Anna Schwendeman, Alan T Remaley, Ajit Jadhav, John JG Tesmer

eLife | ELIFE SCIENCES PUBLICATIONS LTD | Published : 2018

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..

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Grants

Awarded by American Heart Association


Awarded by National Institutes of Health


Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE


Funding Acknowledgements

National Heart, Lung, and Blood Institute Alan T RemaleyNational Center for Advancing Translational Sciences Division of Preclinical Innovation Ajit JadhavAmerican Heart Association 15POST24870001 Kelly A MantheiNational Institutes of Health F32HL131288 Kelly A MantheiAmerican Heart Association 16POST27760002 Wenmin YuanNational Institutes of Health HL071818 John JG TesmerNational Institutes of Health HL122416 John JG TesmerAmerican Heart Association 13SDG17230049 Anna Schwendeman