7rou

Structure of human tyrosyl tRNA synthetase in complex with ML901-Tyr

spinqualitylabelsall models 7rou, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7rou is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: 66I, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SYYC_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. Function SYYC_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 PubMed Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum, namely tyrosine RS (PfYRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901. Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.,Xie SC, Metcalfe RD, Dunn E, Morton CJ, Huang SC, Puhalovich T, Du Y, Wittlin S, Nie S, Luth MR, Ma L, Kim MS, Pasaje CFA, Kumpornsin K, Giannangelo C, Houghton FJ, Churchyard A, Famodimu MT, Barry DC, Gillett DL, Dey S, Kosasih CC, Newman W, Niles JC, Lee MCS, Baum J, Ottilie S, Winzeler EA, Creek DJ, Williamson N, Parker MW, Brand S, Langston SP, Dick LR, Griffin MDW, Gould AE, Tilley L Science. 2022 Jun 3;376(6597):1074-1079. doi: 10.1126/science.abn0611. Epub 2022 , Jun 2. PMID:35653481 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminoacyl tRNA synthetase 3D structures

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