7BY6
Plasmodium vivax cytoplasmic Phenylalanyl-tRNA synthetase in complex with BRD1389
Summary for 7BY6
| Entry DOI | 10.2210/pdb7by6/pdb |
| Descriptor | Phenylalanyl-tRNA synthetase beta chain, putative, (3S,4R,8R,9R,10S)-N-(4-cyclopropyloxyphenyl)-10-(methoxymethyl)-3,4-bis(oxidanyl)-9-[4-(2-phenylethynyl)phenyl]-1,6-diazabicyclo[6.2.0]decane-6-carboxamide, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | aminoacylation, aminoacyl-trna synthetase, trna-binding, atp-binding, auxiliary pocket, heterotetrameric, ligase |
| Biological source | Plasmodium vivax More |
| Total number of polymer chains | 2 |
| Total formula weight | 107447.67 |
| Authors | Malhotra, N.,Manmohan, S.,Harlos, K.,Melillo, B.,Schreiber, S.L.,Manickam, Y.,Sharma, S. (deposition date: 2020-04-21, release date: 2020-11-04, Last modification date: 2023-11-29) |
| Primary citation | Sharma, M.,Malhotra, N.,Yogavel, M.,Harlos, K.,Melillo, B.,Comer, E.,Gonse, A.,Parvez, S.,Mitasev, B.,Fang, F.G.,Schreiber, S.L.,Sharma, A. Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines. Nat Commun, 12:343-343, 2021 Cited by PubMed Abstract: The inhibition of Plasmodium cytosolic phenylalanine tRNA-synthetase (cFRS) by a novel series of bicyclic azetidines has shown the potential to prevent malaria transmission, provide prophylaxis, and offer single-dose cure in animal models of malaria. To date, however, the molecular basis of Plasmodium cFRS inhibition by bicyclic azetidines has remained unknown. Here, we present structural and biochemical evidence that bicyclic azetidines are competitive inhibitors of L-Phe, one of three substrates required for the cFRS-catalyzed aminoacylation reaction that underpins protein synthesis in the parasite. Critically, our co-crystal structure of a PvcFRS-BRD1389 complex shows that the bicyclic azetidine ligand binds to two distinct sub-sites within the PvcFRS catalytic site. The ligand occupies the L-Phe site along with an auxiliary cavity and traverses past the ATP binding site. Given that BRD1389 recognition residues are conserved amongst apicomplexan FRSs, this work lays a structural framework for the development of drugs against both Plasmodium and related apicomplexans. PubMed: 33436639DOI: 10.1038/s41467-020-20478-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.997 Å) |
Structure validation
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