4q93 | pdb_00004q93
Crystal structure of resveratrol bound human tyrosyl tRNA synthetase
Structural highlights
DiseaseSYYC_HUMAN Defects in YARS are the cause of Charcot-Marie-Tooth disease dominant intermediate type C (CMTDIC) [MIM:608323. CMTDIC is a form of Charcot-Marie-Tooth disease characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec.[1] FunctionSYYC_HUMAN Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr) (By similarity). Publication Abstract from PubMedResveratrol 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 A 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. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol.,Sajish M, Schimmel P Nature. 2014 Dec 22. doi: 10.1038/nature14028. PMID:25533949[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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