6POE

Structure of ACLY in complex with CoA

6POE の概要

• エントリーDOI: 10.2210/pdb6poe/pdb
• EMDBエントリー: 20413
• 分子名称: ATP-citrate synthase, COENZYME A (3 entities in total)
• 機能のキーワード: lyase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 487006.70

構造登録者

Wei, X.,Marmorstein, R. (登録日: 2019-07-03, 公開日: 2019-12-25, 最終更新日: 2024-03-20)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.5 Å)