5ZNI

Plasmodium falciparum purine nucleoside phosphorylase in complex with mefloquine

Summary for 5ZNI

• Entry DOI: 10.2210/pdb5zni/pdb
• Descriptor: Purine nucleoside phosphorylase, PHOSPHATE ION, Mefloquine, ... (4 entities in total)
• Functional Keywords: transferase, nucleoside phosphorylase
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum)
• Total number of polymer chains: 1
• Total formula weight: 27364.44

Authors

Chen, D.,Nordlund, P.,Dziekan, J.M. (deposition date: 2018-04-09, release date: 2019-01-16, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)