7DPI

Plasmodium falciparum cytoplasmic Phenylalanyl-tRNA synthetase in complex with BRD7929

Summary for 7DPI

• Entry DOI: 10.2210/pdb7dpi/pdb
• Descriptor: Phenylalanine--tRNA ligase, Phenylalanyl-tRNA synthetase beta subunit, (8R,9S,10S)-10-[(dimethylamino)methyl]-N-(4-methoxyphenyl)-9-[4-(2-phenylethynyl)phenyl]-1,6-diazabicyclo[6.2.0]decane-6-carboxamide, ... (4 entities in total)
• Functional Keywords: aminoacylation, aminoacyl-trna synthetase, trna-binding, atp-binding, auxiliary pocket, heterotetrameric, ligase
• Biological source: Plasmodium falciparum; More
• Total number of polymer chains: 4
• Total formula weight: 219180.68

Authors

Manmohan, S.,Malhotra, N.,Harlos, K.,Manickam, Y.,Sharma, A. (deposition date: 2020-12-19, release date: 2022-03-23, Last modification date: 2024-05-29)

Primary citation

Sharma, M.,Mutharasappan, N.,Manickam, Y.,Harlos, K.,Melillo, B.,Comer, E.,Tabassum, H.,Parvez, S.,Schreiber, S.L.,Sharma, A.
Inhibition of Plasmodium falciparum phenylalanine tRNA synthetase provides opportunity for antimalarial drug development.
Structure, 30:962-972.e3, 2022

PubMed Abstract: Bicyclic azetidine compounds possess antimalarial activity via targeting of the cytoplasmic Plasmodium falciparum (Pf) protein translation enzyme phenylalanine-tRNA synthetase (cFRS). These drugs kill parasites both in vitro and in vivo, including the blood, liver, and transmission developmental stages. Here we present the co-crystal structure of PfcFRS with a potent inhibitor, the bicyclic azetidine BRD7929. Our studies reveal high-affinity binding of BRD7929 with PfcFRS along with exquisite specificity compared with the human enzyme, leading in turn to potent and selective inhibition of the parasite enzyme. Our co-crystal structure shows that BRD7929 binds in the active site in the α subunit of PfcFRS, where it occupies the amino acid site, an auxiliary site, and partially the ATP site. This structural snapshot of inhibitor-bound PfcFRS thus provides a platform for the structure-guided optimization of novel antimalarial compounds.

PubMed: 35460612
DOI: 10.1016/j.str.2022.03.017

Experimental method

X-RAY DIFFRACTION (3.597 Å)