7DI7

Falcilysin in complex with chloroquine

7DI7 の概要

• エントリーDOI: 10.2210/pdb7di7/pdb
• 分子名称: Falcilysin, ACETATE ION, N4-(7-CHLORO-QUINOLIN-4-YL)-N1,N1-DIETHYL-PENTANE-1,4-DIAMINE, ... (5 entities in total)
• 機能のキーワード: protein binding-inhibitor complex, protein binding/inhibitor
• 由来する生物種: Plasmodium falciparum 3D7
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 135542.73

構造登録者

Lin, J.Q.,El Sahili, A.,Lescar, J. (登録日: 2020-11-18, 公開日: 2021-12-01, 最終更新日: 2024-05-29)

主引用文献

Wirjanata, G.,Lin, J.,Dziekan, J.M.,El Sahili, A.,Chung, Z.,Tjia, S.,Binte Zulkifli, N.E.,Boentoro, J.,Tham, R.,Jia, L.S.,Go, K.D.,Yu, H.,Partridge, A.,Olsen, D.,Prabhu, N.,Sobota, R.M.,Nordlund, P.,Lescar, J.,Bozdech, Z.
Identification of an inhibitory pocket in falcilysin provides a new avenue for malaria drug development.
Cell Chem Biol, 31:743-759.e8, 2024

PubMed Abstract: Identification of new druggable protein targets remains the key challenge in the current antimalarial development efforts. Here we used mass-spectrometry-based cellular thermal shift assay (MS-CETSA) to identify potential targets of several antimalarials and drug candidates. We found that falcilysin (FLN) is a common binding partner for several drug candidates such as MK-4815, MMV000848, and MMV665806 but also interacts with quinoline drugs such as chloroquine and mefloquine. Enzymatic assays showed that these compounds can inhibit FLN proteolytic activity. Their interaction with FLN was explored systematically by isothermal titration calorimetry and X-ray crystallography, revealing a shared hydrophobic pocket in the catalytic chamber of the enzyme. Characterization of transgenic cell lines with lowered FLN expression demonstrated statistically significant increases in susceptibility toward MK-4815, MMV000848, and several quinolines. Importantly, the hydrophobic pocket of FLN appears amenable to inhibition and the structures reported here can guide the development of novel drugs against malaria.

PubMed: 38593807
DOI: 10.1016/j.chembiol.2024.03.002

実験手法

X-RAY DIFFRACTION (1.82 Å)