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-Structure paper
タイトル | Allosteric role of the citrate synthase homology domain of ATP citrate lyase. |
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ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 2247, Year 2023 |
掲載日 | 2023年4月19日 |
著者 | Xuepeng Wei / Kollin Schultz / Hannah L Pepper / Emily Megill / Austin Vogt / Nathaniel W Snyder / Ronen Marmorstein / |
PubMed 要旨 | ATP citrate lyase (ACLY) is the predominant nucleocytosolic source of acetyl-CoA and is aberrantly regulated in many diseases making it an attractive therapeutic target. Structural studies of ACLY ...ATP citrate lyase (ACLY) is the predominant nucleocytosolic source of acetyl-CoA and is aberrantly regulated in many diseases making it an attractive therapeutic target. Structural studies of ACLY reveal a central homotetrameric core citrate synthase homology (CSH) module flanked by acyl-CoA synthetase homology (ASH) domains, with ATP and citrate binding the ASH domain and CoA binding the ASH-CSH interface to produce acetyl-CoA and oxaloacetate products. The specific catalytic role of the CSH module and an essential D1026A residue contained within it has been a matter of debate. Here, we report biochemical and structural analysis of an ACLY-D1026A mutant demonstrating that this mutant traps a (3S)-citryl-CoA intermediate in the ASH domain in a configuration that is incompatible with the formation of acetyl-CoA, is able to convert acetyl-CoA and OAA to (3S)-citryl-CoA in the ASH domain, and can load CoA and unload acetyl-CoA in the CSH module. Together, this data support an allosteric role for the CSH module in ACLY catalysis. |
リンク | Nat Commun / PubMed:37076498 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.2 - 2.8 Å |
構造データ | EMDB-24479, PDB-7rig: EMDB-24511, PDB-7rkz: EMDB-24577, PDB-7rmp: EMDB-29668, PDB-8g1e: EMDB-29669, PDB-8g1f: EMDB-29739, PDB-8g5c: EMDB-29740, PDB-8g5d: |
化合物 | ChemComp-ADP: ChemComp-Q5B: ChemComp-FLC:
ChemComp-UNL: ChemComp-COA: ChemComp-PO4: ChemComp-HOH: ChemComp-ACO: ChemComp-OAA: |
由来 |
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キーワード | TRANSFERASE / mutant / LYASE |