Structures of plasmepsin X from P. falciparum reveal a novel inactivation mechanism of the zymogen and molecular basis for binding of inhibitors in mature enzyme

Author:

Kesari, Pooja [ORCID]

Deshmukh, Anuradha

Pahelkar, Nikhil

Suryawanshi, Abhishek B

Rathore, Ishan

Mishra, Vandana

Dupuis, John H

Xiao, Huogen

Gustchina,Alla

Abendroth, Jan

Labaied, Mehdi

Yada, Rickey Y

Wlodawer, Alexander [ORCID]

Edwards, Thomas E

Lorimer, Donald D

Bhaumik, Prasenjit [ORCID]
Author Address

Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Food, Nutrition, and Health Program, Faculty of Land and Food Systems, University of British Columbia, 248-2357 Main Mall Vancouver, British Columbia, Vancouver, Canada., Summerland Research and Development Center, Agriculture and Agri-Food Canada, Summerland, British Columbia, Canada., Protein Structure Section, Center for Structural Biology, National Cancer Institute, Frederick, Maryland, USA., UCB Pharma, Bainbridge Island, WA, USA., Seattle Structural Genomics Center for Infectious Disease.,

Abstract:

Plasmodium falciparum plasmepsin X (PfPMX), involved in the invasion and egress of this deadliest malarial parasite, is essential for its survival and hence considered as an important drug target. We report the first crystal structure of PfPMX zymogen containing a novel fold of its prosegment. A unique twisted loop from the prosegment and arginine 244 from the mature enzyme are involved in zymogen inactivation; such mechanism, not previously reported, might be common for apicomplexan proteases similar to PfPMX. The maturation of PfPMX zymogen occurs through cleavage of its prosegment at multiple sites. Our data provide thorough insights into the mode of binding of a substrate and a potent inhibitor 49c to PfPMX. We present molecular details of inactivation, maturation, and inhibition of PfPMX that should aid in the development of potent inhibitors against pepsin-like aspartic proteases from apicomplexan parasites. This article is protected by copyright. All rights reserved. © 2022 The Protein Society.

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