Journal article
Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax
AN Hodder, J Christensen, S Scally, T Triglia, A Ngo, RW Birkinshaw, B Bailey, P Favuzza, MH Dietrich, WH Tham, PE Czabotar, K Lowes, Z Guo, N Murgolo, MD Lera Ruiz, JA McCauley, BE Sleebs, D Olsen, AF Cowman
Structure | Published : 2022
Abstract
Plasmepsins IX (PMIX) and X (PMX) are essential aspartyl proteases for Plasmodium spp. egress, invasion, and development. WM4 and WM382 inhibit PMIX and PMX in Plasmodium falciparum and P. vivax. WM4 inhibits PMX, while WM382 is a dual inhibitor of PMIX and PMX. To understand their function, we identified protein substrates. Enzyme kinetic and structural analyses identified interactions responsible for drug specificity. PMIX and PMX have similar substrate specificity; however, there are distinct differences for peptide and protein substrates. Differences in WM4 and WM382 binding for PMIX and PMX map to variations in the S' region and engagement of the active site S3 pocket. Structures of PMX..
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Awarded by Merck
Funding Acknowledgements
We thank Red Cross Blood Service (Melbourne) for blood. This work was sup- ported by The Wellcome Trust (109662/Z/15/Z and 202749/Z/16/Z) , Victorian State Government Operational Infrastructure Support, Australian Government NHMRC IRIISS, and National Health and Medical Research Council of Australia. This research used MX2 beamline at Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. We acknowledge CSIRO Collaborative Crystallisation Centre (http:// www.csiro.au/C3; Melbourne, Australia) for crystallization.