8TC8

Human asparaginyl-tRNA synthetase bound to adenosine 5'-sulfamate

Summary for 8TC8

• Entry DOI: 10.2210/pdb8tc8/pdb
• Descriptor: Asparagine--tRNA ligase, cytoplasmic, 5'-O-[N-(L-ASPARAGINYL)SULFAMOYL]ADENOSINE, GLYCEROL, ... (5 entities in total)
• Functional Keywords: enzyme, ligase, synthase, drug target
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 255518.37

Authors

Dogovski, C.,Metcalfe, R.D.,Xie, S.C.,Morton, C.J.,Tilley, L.,Griffin, M.D.W. (deposition date: 2023-06-30, release date: 2024-02-07, Last modification date: 2024-02-14)

Primary citation

Xie, S.C.,Wang, Y.,Morton, C.J.,Metcalfe, R.D.,Dogovski, C.,Pasaje, C.F.A.,Dunn, E.,Luth, M.R.,Kumpornsin, K.,Istvan, E.S.,Park, J.S.,Fairhurst, K.J.,Ketprasit, N.,Yeo, T.,Yildirim, O.,Bhebhe, M.N.,Klug, D.M.,Rutledge, P.J.,Godoy, L.C.,Dey, S.,De Souza, M.L.,Siqueira-Neto, J.L.,Du, Y.,Puhalovich, T.,Amini, M.,Shami, G.,Loesbanluechai, D.,Nie, S.,Williamson, N.,Jana, G.P.,Maity, B.C.,Thomson, P.,Foley, T.,Tan, D.S.,Niles, J.C.,Han, B.W.,Goldberg, D.E.,Burrows, J.,Fidock, D.A.,Lee, M.C.S.,Winzeler, E.A.,Griffin, M.D.W.,Todd, M.H.,Tilley, L.
Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.
Nat Commun, 15:937-937, 2024

PubMed Abstract: Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

PubMed: 38297033
DOI: 10.1038/s41467-024-45224-z

Experimental method

X-RAY DIFFRACTION (1.9 Å)