4ZL4

Plasmepsin V from Plasmodium vivax bound to a transition state mimetic (WEHI-842)

Summary for 4ZL4

• Entry DOI: 10.2210/pdb4zl4/pdb
• Related PRD ID: PRD_002168
• Descriptor: Aspartic protease PM5, N-[(benzyloxy)carbonyl]-O-carbamimidamido-L-homoseryl-N-{(3S,4S)-3-hydroxy-6-methyl-1-oxo-1-[(2-phenylethyl)amino]heptan-4-yl}-L-valinamide, SULFATE ION, ... (6 entities in total)
• Functional Keywords: malaria, inhibitor, aspartyl protease, pexel, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Plasmodium vivax
• Total number of polymer chains: 2
• Total formula weight: 103740.46

Authors

Czabotar, P.E.,Hodder, A.N.,Smith, B.J.,Sleebs, B.E.,Gazdic, M.,Boddey, J.A.,Cowman, A.F. (deposition date: 2015-05-01, release date: 2015-07-15, Last modification date: 2024-10-23)

Primary citation

Hodder, A.N.,Sleebs, B.E.,Czabotar, P.E.,Gazdik, M.,Xu, Y.,O'Neill, M.T.,Lopaticki, S.,Nebl, T.,Triglia, T.,Smith, B.J.,Lowes, K.,Boddey, J.A.,Cowman, A.F.
Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes.
Nat.Struct.Mol.Biol., 22:590-596, 2015

PubMed Abstract: Plasmepsin V, an essential aspartyl protease of malaria parasites, has a key role in the export of effector proteins to parasite-infected erythrocytes. Consequently, it is an important drug target for the two most virulent malaria parasites of humans, Plasmodium falciparum and Plasmodium vivax. We developed a potent inhibitor of plasmepsin V, called WEHI-842, which directly mimics the Plasmodium export element (PEXEL). WEHI-842 inhibits recombinant plasmepsin V with a half-maximal inhibitory concentration of 0.2 nM, efficiently blocks protein export and inhibits parasite growth. We obtained the structure of P. vivax plasmepsin V in complex with WEHI-842 to 2.4-Å resolution, which provides an explanation for the strict requirements for substrate and inhibitor binding. The structure characterizes both a plant-like fold and a malaria-specific helix-turn-helix motif that are likely to be important in cleavage of effector substrates for export.

PubMed: 26214367
DOI: 10.1038/nsmb.3061

Experimental method

X-RAY DIFFRACTION (2.37 Å)