8G5D

Structure of ACLY-D1026A-products, local refinement of ASH domain

Summary for 8G5D

• Entry DOI: 10.2210/pdb8g5d/pdb
• EMDB information: 29669 29740
• Descriptor: ATP-citrate synthase, ACETYL COENZYME *A, OXALOACETATE ION, ... (7 entities in total)
• Functional Keywords: mutant, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 488986.85

Authors

Wei, X.,Marmorstein, R. (deposition date: 2023-02-13, release date: 2023-05-10, Last modification date: 2024-06-19)

Primary citation

Wei, X.,Schultz, K.,Pepper, H.L.,Megill, E.,Vogt, A.,Snyder, N.W.,Marmorstein, R.
Allosteric role of the citrate synthase homology domain of ATP citrate lyase.
Nat Commun, 14:2247-2247, 2023

PubMed Abstract: 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.

PubMed: 37076498
DOI: 10.1038/s41467-023-37986-9

Experimental method

ELECTRON MICROSCOPY (2.5 Å)