4Q93

Crystal structure of resveratrol bound human tyrosyl tRNA synthetase

Summary for 4Q93

• Entry DOI: 10.2210/pdb4q93/pdb
• Related: 1N3L 1Q11 4QBT
• Descriptor: Tyrosine--tRNA ligase, cytoplasmic, RESVERATROL, SULFATE ION, ... (7 entities in total)
• Functional Keywords: resveratrol, aminoacyl trna synthetases, amino acid activation, active site, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 43347.76

Authors

Mathew, S.,Schimmel, P. (deposition date: 2014-04-28, release date: 2014-12-17, Last modification date: 2023-09-20)

Primary citation

Sajish, M.,Schimmel, P.
A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol.
Nature, 519:370-373, 2014

PubMed Abstract: Resveratrol is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects by initiating a stress response that induces survival genes. Because human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions, we considered the possibility that the tyrosine-like phenolic ring of resveratrol might fit into the active site pocket to effect a nuclear role. Here we present a 2.1 Å co-crystal structure of resveratrol bound to the active site of TyrRS. Resveratrol nullifies the catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD(+)-dependent auto-poly-ADP-ribosylation of poly(ADP-ribose) polymerase 1 (PARP1). Downstream activation of key stress signalling pathways are causally connected to TyrRS-PARP1-NAD(+) collaboration. This collaboration is also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analogue. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites, here a non-spliced TyrRS catalytic null reveals a new PARP1- and NAD(+)-dependent dimension to the physiological mechanism of resveratrol.

PubMed: 25533949
DOI: 10.1038/nature14028

Experimental method

X-RAY DIFFRACTION (2.1 Å)