6C4G

Plasmepsin V from Plasmodium vivax bound to a transition state mimetic (WEHI-601)

Summary for 6C4G

• Entry DOI: 10.2210/pdb6c4g/pdb
• Related PRD ID: PRD_002302
• Descriptor: Aspartic protease PM5, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: malaria, protease, inhibitor, plasmepsin, hydrolase
• Biological source: Plasmodium vivax (malaria parasite P. vivax)
• Total number of polymer chains: 1
• Total formula weight: 52061.98

Authors

Czabotar, P.E.,Hodder, A.N.,Nguyen, W.,Sleebs, B.E.,Boddey, J.A.,Cowman, A.F. (deposition date: 2018-01-11, release date: 2018-06-13, Last modification date: 2024-10-16)

Primary citation

Nguyen, W.,Hodder, A.N.,de Lezongard, R.B.,Czabotar, P.E.,Jarman, K.E.,O'Neill, M.T.,Thompson, J.K.,Jousset Sabroux, H.,Cowman, A.F.,Boddey, J.A.,Sleebs, B.E.
Enhanced antimalarial activity of plasmepsin V inhibitors by modification of the P2position of PEXEL peptidomimetics.
Eur J Med Chem, 154:182-198, 2018

PubMed Abstract: Plasmepsin V is an aspartyl protease that plays a critical role in the export of proteins bearing the Plasmodium export element (PEXEL) motif (RxLxQ/E/D) to the infected host erythrocyte, and thus the survival of the malaria parasite. Previously, development of transition state PEXEL mimetic inhibitors of plasmepsin V have primarily focused on demonstrating the importance of the P Arg and P Leu in binding affinity and selectivity. Here, we investigate the importance of the P position by incorporating both natural and non-natural amino acids into this position and show disubstituted beta-carbon amino acids convey the greatest potency. Consequently, we show analogues with either cyclohexylglycine or phenylglycine in the P position are the most potent inhibitors of plasmepsin V that impair processing of the PEXEL motif in exported proteins resulting in death of P. falciparum asexual stage parasites.

PubMed: 29800827
DOI: 10.1016/j.ejmech.2018.05.022

Experimental method

X-RAY DIFFRACTION (2.39 Å)