9DPD

Cryo-EM structure of SerRS dimer in complex with one SIRT2

Summary for 9DPD

• Entry DOI: 10.2210/pdb9dpd/pdb
• EMDB information: 47103
• Descriptor: Serine--tRNA ligase, cytoplasmic, NAD-dependent protein deacetylase sirtuin-2, [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL[HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE (3 entities in total)
• Functional Keywords: complex, enzyme, translation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 161518.84

Authors

Yang, J.,Zhang, Q.,Zhang, H.,Lander, G.C.,Yang, X. (deposition date: 2024-09-21, release date: 2026-03-18, Last modification date: 2026-09-30)

Primary citation

Zhang, Q.,Zhang, H.,Hirschi, M.,Li, S.,Lander, G.C.,Yang, J.,Yang, X.L.
A metabolite-bridged complex between SerRS and SIRT2 couples NAD+ metabolism to translation control.
Nat Commun, 17:-, 2026

PubMed Abstract: Cellular homeostasis requires tight coordination between metabolic and translational networks. Here we identify a direct molecular link between these processes through a cryo-EM structure of human cytosolic seryl-tRNA synthetase (SerRS) in complex with the NAD⁺-dependent deacetylase SIRT2. This interaction is promoted by the NAD⁺ metabolite ADP-ribose (ADPR), which acts as a molecular bridge between the two enzymes. Within the SIRT2 active site, ADPR engages SerRS residue K414 located in a flexible catalytic-domain loop. Acetylation of K414 is dispensable for binding. Functionally, complex formation inhibits SIRT2 deacetylase activity by blocking substrate access, while SIRT2 association suppresses SerRS aminoacylation activity by preventing tRNA binding. Thus, SerRS and SIRT2 mutually regulate each other, with ADPR enhancing while tRNA attenuating their interaction. Oxidative stress promotes this interaction via a PARP1-dependent pathway, revealing an ADPR-responsive regulatory module that couples metabolic state to translational output. This regulatory module is likely conserved across vertebrates.

PubMed: 42420298
DOI: 10.1038/s41467-026-75266-4

Experimental method

ELECTRON MICROSCOPY (3.87 Å)