7BY6

Plasmodium vivax cytoplasmic Phenylalanyl-tRNA synthetase in complex with BRD1389

7BY6 の概要

• エントリーDOI: 10.2210/pdb7by6/pdb
• 分子名称: 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)
• 機能のキーワード: aminoacylation, aminoacyl-trna synthetase, trna-binding, atp-binding, auxiliary pocket, heterotetrameric, ligase
• 由来する生物種: Plasmodium vivax; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 107447.67

構造登録者

Malhotra, N.,Manmohan, S.,Harlos, K.,Melillo, B.,Schreiber, S.L.,Manickam, Y.,Sharma, S. (登録日: 2020-04-21, 公開日: 2020-11-04, 最終更新日: 2023-11-29)

主引用文献

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

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: 33436639
DOI: 10.1038/s41467-020-20478-5

実験手法

X-RAY DIFFRACTION (2.997 Å)