9CLL

Plasmodium falciparum tyrosyl-tRNA synthetase in complex with ML471-Tyr

This is a non-PDB format compatible entry.

Summary for 9CLL

• Entry DOI: 10.2210/pdb9cll/pdb
• Descriptor: tyrosine--tRNA ligase, {(2R,3S,4R,5R)-5-[4-amino-3-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-3,4-dihydroxyoxolan-2-yl}methyl [(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]sulfamate, MALONATE ION, ... (6 entities in total)
• Functional Keywords: inhibitor complex, ligase, ligase-inhibitor complex, ligase/inhibitor
• Biological source: Plasmodium falciparum 3D7
• Total number of polymer chains: 2
• Total formula weight: 88498.56

Authors

Tai, C.W.,Dogovski, C.,Xie, S.C.,Tilley, L.,Griffin, M.D.W. (deposition date: 2024-07-11, release date: 2024-11-27, Last modification date: 2025-06-11)

Primary citation

Xie, S.C.,Tai, C.W.,Morton, C.J.,Ma, L.,Huang, S.C.,Wittlin, S.,Du, Y.,Hu, Y.,Dogovski, C.,Salimimarand, M.,Griffin, R.,England, D.,de la Cruz, E.,Deni, I.,Yeo, T.,Burkhard, A.Y.,Striepen, J.,Schindler, K.A.,Crespo, B.,Gamo, F.J.,Khandokar, Y.,Hutton, C.A.,Rabie, T.,Birkholtz, L.M.,Famodimu, M.T.,Delves, M.J.,Bolsher, J.,Koolen, K.M.J.,van der Laak, R.,Aguiar, A.C.C.,Pereira, D.B.,Guido, R.V.C.,Creek, D.J.,Fidock, D.A.,Dick, L.R.,Brand, S.L.,Gould, A.E.,Langston, S.,Griffin, M.D.W.,Tilley, L.
A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo.
Plos Pathog., 20:e1012429-e1012429, 2024

PubMed Abstract: The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent reaction hijacking inhibitor of PfTyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity. We explored a series of ML901 analogues and identified ML471, which exhibits improved potency against trophozoites and enhanced selectivity against a human cell line. Additionally, it has no inhibitory activity against human ubiquitin-activating enzyme (UAE) in vitro. ML471 exhibits low nanomolar activity against asexual blood stage P. falciparum and potent activity against liver stage parasites, gametocytes and transmissible gametes. It is fast-acting and exhibits a long in vivo half-life. ML471 is well-tolerated and shows single dose oral efficacy in the SCID mouse model of P. falciparum malaria. We confirm that ML471 is a reaction hijacking inhibitor that is converted into a tight binding Tyr-ML471 conjugate by the PfTyrRS enzyme. A crystal structure of the PfTyrRS/ Tyr-ML471 complex offers insights into improved potency, while molecular docking into UAE provides a rationale for improved selectivity.

PubMed: 39652589
DOI: 10.1371/journal.ppat.1012429

Experimental method

X-RAY DIFFRACTION (1.8 Å)