Structures of plasmepsin X from Plasmodium falciparum reveal a novel inactivation mechanism of the zymogen and molecular basis for binding of inhibitors in mature enzyme. (5th February 2022)

• Record Type: Journal Article
• Authors: Kesari, Pooja; 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; Edwards, Thomas E.; Lorimer, Donald D.; Bhaumik, Prasenjit
• Is Part Of: Protein science. Volume 31:Number 4(2022)
• Page Start: 882
• Page End: 899
• Publication Date: 2022-02-05
• Subjects: 49c inhibitor -- apicomplexan parasite -- P. falciparum -- plasmepsin X -- zymogen; Proteins -- Periodicals; 572.6
• DOI: 10.1002/pro.4279
• Languages: English
• ISSNs: 0961-8368

Abstract

Abstract: Plasmodium falciparum plasmepsin X ( Pf PMX), 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 Pf PMX zymogen containing a novel fold of its prosegment. A unique twisted loop from the prosegment and arginine 244 from the mature enzyme is involved in zymogen inactivation; such mechanism, not previously reported, might be common for apicomplexan proteases similar to Pf PMX. The maturation of Pf PMX 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 Pf PMX. We present molecular details of inactivation, maturation, and inhibition of Pf PMX that should aid in the development of potent inhibitors against pepsin‐like aspartic proteases from apicomplexan parasites. Abstract : PDB Code(s): 7RY7 ;