Molecular mechanisms and inhibition of metabolic acyltransferase enzymes
EMSL Project ID
51276
Abstract
The goal of this project is to determine the cryo-EM structures of metabolic acyltransferase enzymes in functionally relevant reaction states and bound to inhibitors to elucidate their molecular mechanism of catalysis and to facilitate structure-based drug development for therapy. We are currently focusing on ATP-citrate lyase (ACLY) and acetyl-CoA synthetase short-chain family member 2 (ACSS2), the nucleo-cytosolic sources of acetyl-CoA, a fundamental building block of eukaryotic carbon metabolism. ACLY and ACSS2 are aberrantly regulated in many cancers, cardiovascular disease, and metabolic disorders, making these enzymes attractive drug targets. We recently reported the single particle cryo-EM reconstruction of the intact human ACLY tetramer alone and bound to substrates, products and reaction intermediates, and will now prepare cryo-EM grids of ACLY bound to three inhibitors for cryo-EM reconstruction. The structure of human ACSS2 is not known. We will prepare cryo-EM grids of human ACSS2 bound to substrates and inhibitors for cryo-EM reconstruction.
Project Details
Start Date
2020-02-15
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members