5ZNI

Plasmodium falciparum purine nucleoside phosphorylase in complex with mefloquine

5ZNI の概要

• エントリーDOI: 10.2210/pdb5zni/pdb
• 分子名称: Purine nucleoside phosphorylase, PHOSPHATE ION, (11R,12S)- Mefloquine, ... (4 entities in total)
• 機能のキーワード: transferase, nucleoside phosphorylase
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27364.44

構造登録者

Chen, D.,Nordlund, P.,Dziekan, J.M. (登録日: 2018-04-09, 公開日: 2019-01-16, 最終更新日: 2024-11-13)

主引用文献

Dziekan, J.M.,Yu, H.,Chen, D.,Dai, L.,Wirjanata, G.,Larsson, A.,Prabhu, N.,Sobota, R.M.,Bozdech, Z.,Nordlund, P.
Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay.
Sci Transl Med, 11:-, 2019

PubMed Abstract: Mechanisms of action (MoAs) have been elusive for most antimalarial drugs in clinical use. Decreasing responsiveness to antimalarial treatments stresses the need for a better resolved understanding of their MoAs and associated resistance mechanisms. In the present work, we implemented the cellular thermal shift assay coupled with mass spectrometry (MS-CETSA) for drug target identification in , the main causative agent of human malaria. We validated the efficacy of this approach for pyrimethamine, a folic acid antagonist, and E64d, a broad-spectrum cysteine proteinase inhibitor. Subsequently, we applied MS-CETSA to quinine and mefloquine, two important antimalarial drugs with poorly characterized MoAs. Combining studies in the parasite lysate and intact infected red blood cells, we found purine nucleoside phosphorylase (PfPNP) as a common binding target for these two quinoline drugs. Biophysical and structural studies with a recombinant protein further established that both compounds bind within the enzyme's active site. Quinine binds to PfPNP at low nanomolar affinity, suggesting a substantial contribution to its therapeutic effect. Overall, we demonstrated that implementation of MS-CETSA for constitutes a promising strategy to elucidate the MoAs of existing and candidate antimalarial drugs.

PubMed: 30602534
DOI: 10.1126/scitranslmed.aau3174

実験手法

X-RAY DIFFRACTION (2.3 Å)