7ROU
Structure of human tyrosyl tRNA synthetase in complex with ML901-Tyr
Summary for 7ROU
| Entry DOI | 10.2210/pdb7rou/pdb |
| Descriptor | Tyrosine--tRNA ligase, cytoplasmic, {(2R,3S,4R,5R)-5-[4-amino-3-(difluoromethoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-3,4-dihydroxyoxolan-2-yl}methyl [(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]sulfamate (non-preferred name), SULFATE ION, ... (4 entities in total) |
| Functional Keywords | enzyme, tyrosyl-trna synthetase, malaria, inhibitor, ligase, tyrosine-amp |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 42367.41 |
| Authors | Metcalfe, R.D.,Xie, S.C.,Morton, C.J.,Tilley, L.,Griffin, M.D.W. (deposition date: 2021-08-02, release date: 2022-06-08, Last modification date: 2023-10-18) |
| Primary citation | Xie, S.C.,Metcalfe, R.D.,Dunn, E.,Morton, C.J.,Huang, S.C.,Puhalovich, T.,Du, Y.,Wittlin, S.,Nie, S.,Luth, M.R.,Ma, L.,Kim, M.S.,Pasaje, C.F.A.,Kumpornsin, K.,Giannangelo, C.,Houghton, F.J.,Churchyard, A.,Famodimu, M.T.,Barry, D.C.,Gillett, D.L.,Dey, S.,Kosasih, C.C.,Newman, W.,Niles, J.C.,Lee, M.C.S.,Baum, J.,Ottilie, S.,Winzeler, E.A.,Creek, D.J.,Williamson, N.,Parker, M.W.,Brand, S.,Langston, S.P.,Dick, L.R.,Griffin, M.D.W.,Gould, A.E.,Tilley, L. Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy. Science, 376:1074-1079, 2022 Cited by PubMed Abstract: 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 , namely tyrosine RS (YRS). 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. PubMed: 35653481DOI: 10.1126/science.abn0611 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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