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Cryo-EM structure of the human ATP-citrate lyase (ACLY) bound to inhibitors


EMSL Project ID
50905

Abstract

The goal of this project is to determine the cryo-EM structure of the human ATP-citrate lyase (ACLY) multimer bound to inhibitors to better understand the mechanism of ACLY activity and to generate a molecular scaffold for structure-based development of improved inhibitors. ACLY is the major source of nucleocytosolic acetyl-CoA, a fundamental building block of carbon metabolism in eukaryotes. ACLY is aberrantly regulated in many cancers, cardiovascular disease, and metabolic disorders; and an ACLY prodrug, bempedoic acid is currently in phase III clinical trials to reduce LDL cholesterol for patients with atherosclerotic cardiovascular risk. We recently determined the single particle Cryo-EM reconstruction of the intact 480 kDa ACLY tetramer alone and bound to citrate and CoA cofactors, which now positions us for the structure-based development of ACLY inhibitors. We have obtained two inhibitors from our collaborators at GlaxoSmithKline (GSK) with reported IC50 values of 300 nM (GSK1) and 10 nM (GSK2) and have prepare grids of ACLY bound to these inhibitors. We will also prepare the active CoA-bempedoic acid adduct (ETC-1002-CoA) for preparation of an ACLY/ETC-1002-CoA complex for Cryo-EM grid preparation. Here, we propose to determine the single particle Cryo-EM reconstruction of ACLY bound to these three inhibitors. These structures will provide a molecular scaffold for the structure-based development of more potent and selective ACLY inhibitors for therapeutic applications.

Project Details

Start Date
2019-05-15
End Date
2020-02-29
Status
Closed

Team

Principal Investigator

Ronen Marmorstein
Institution
University of Pennsylvania

Team Members

Xuepeng Wei
Institution
University of Pennsylvania

Nancy Meyer
Institution
Oregon Health & Science University