6UUW

Structure of human ATP citrate lyase E599Q mutant in complex with Mg2+, citrate, ATP and CoA

Summary for 6UUW

• Entry DOI: 10.2210/pdb6uuw/pdb
• EMDB information: 20902
• Descriptor: ATP-citrate synthase, ADENOSINE-5'-DIPHOSPHATE, COENZYME A, ... (6 entities in total)
• Functional Keywords: lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 489799.92

Authors

Wei, X.,Marmorstein, R. (deposition date: 2019-11-01, release date: 2019-12-25, Last modification date: 2024-05-29)

Primary citation

Wei, X.,Schultz, K.,Bazilevsky, G.A.,Vogt, A.,Marmorstein, R.
Molecular basis for acetyl-CoA production by ATP-citrate lyase
Nat.Struct.Mol.Biol., 27:33-41, 2020

PubMed Abstract: ATP-citrate lyase (ACLY) synthesizes cytosolic acetyl coenzyme A (acetyl-CoA), a fundamental cellular building block. Accordingly, aberrant ACLY activity is observed in many diseases. Here we report cryo-EM structures of human ACLY, alone or bound to substrates or products. ACLY forms a homotetramer with a rigid citrate synthase homology (CSH) module, flanked by four flexible acetyl-CoA synthetase homology (ASH) domains; CoA is bound at the CSH-ASH interface in mutually exclusive productive or unproductive conformations. The structure of a catalytic mutant of ACLY in the presence of ATP, citrate and CoA substrates reveals a phospho-citryl-CoA intermediate in the ASH domain. ACLY with acetyl-CoA and oxaloacetate products shows the products bound in the ASH domain, with an additional oxaloacetate in the CSH domain, which could function in ACLY autoinhibition. These structures, which are supported by biochemical and biophysical data, challenge previous proposals of the ACLY catalytic mechanism and suggest additional therapeutic possibilities for ACLY-associated metabolic disorders.

PubMed: 31873304
DOI: 10.1038/s41594-019-0351-6

Experimental method

ELECTRON MICROSCOPY (2.85 Å)