7VE2

Crystal Structure of Lopinavir bound Plasmepsin II (PMII) from Plasmodium falciparum

Summary for 7VE2

• Entry DOI: 10.2210/pdb7ve2/pdb
• Descriptor: Plasmepsin II, N-{1-BENZYL-4-[2-(2,6-DIMETHYL-PHENOXY)-ACETYLAMINO]-3-HYDROXY-5-PHENYL-PENTYL}-3-METHYL-2-(2-OXO-TETRAHYDRO-PYRIMIDIN-1-YL)-BUTYRAMIDE, 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE (3 entities in total)
• Functional Keywords: inhibitor, protease, peptidomimetic, hiv-1 protease inhibitor, peptidase, hemoglobin degrader, hydrolase
• Biological source: Plasmodium falciparum (isolate 3D7)
• Total number of polymer chains: 1
• Total formula weight: 38972.48

Authors

Mishra, V.,Rathore, I.,Bhaumik, P. (deposition date: 2021-09-07, release date: 2023-02-01, Last modification date: 2024-10-16)

Primary citation

Mishra, V.,Deshmukh, A.,Rathore, I.,Chakraborty, S.,Patankar, S.,Gustchina, A.,Wlodawer, A.,Yada, R.Y.,Bhaumik, P.
Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery.
Curr Res Struct Biol, 7:100128-100128, 2024

PubMed Abstract: species are causative agents of malaria, a disease that is a serious global health concern. FDA-approved HIV-1 protease inhibitors (HIV-1 PIs) have been reported to be effective in reducing the infection by parasites in the population co-infected with both HIV-1 and malaria. However, the mechanism of HIV-1 PIs in mitigating pathogenesis during malaria/HIV-1 co-infection is not fully understood. In this study we demonstrate that HIV-1 drugs ritonavir (RTV) and lopinavir (LPV) exhibit the highest inhibition activity against plasmepsin II (PMII) and plasmepsin X (PMX) of Crystal structures of the complexes of PMII with both drugs have been determined. The inhibitors interact with PMII multiple hydrogen bonding and hydrophobic interactions. The P4 moiety of RTV forms additional interactions compared to LPV and exhibits conformational flexibility in a large S4 pocket of PMII. Our study is also the first to report inhibition of PMX by RTV and the mode of binding of the drug to the PMX active site. Analysis of the crystal structures implies that PMs can accommodate bulkier groups of these inhibitors in their S4 binding pockets. Structurally similar active sites of different vacuolar and non-vacuolar PMs suggest the potential of HIV-1 PIs in targeting these enzymes with differential affinities. Our structural investigations and biochemical data emphasize PMs as crucial targets for repurposing HIV-1 PIs as antimalarial drugs.

PubMed: 38304146
DOI: 10.1016/j.crstbi.2024.100128

Experimental method

X-RAY DIFFRACTION (3.2 Å)