更新于：2024-11-01

PfPMX

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与 PfPMX 相关的药物

PfGAP3KO

靶点

PfPMX

作用机制

PfPMX modulators

在研机构

University of Washington [+1]

原研机构

University of Washington

在研适应症

疟疾

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

Compound 49c(University of Geneva)

靶点

PfPMX

作用机制

PfPMX抑制剂

在研机构

University of Geneva

原研机构

University of Geneva

在研适应症

疟疾

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

WM-382

靶点

PfPMX

作用机制

PfPMX抑制剂

在研机构

The Walter & Eliza Hall Institute of Medical Research [+1]

原研机构

Merck & Co., Inc. [+1]

在研适应症

疟疾

非在研适应症

恶性疟 [+1]

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PfPMX 相关的临床结果

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100 项与 PfPMX 相关的转化医学

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0 项与 PfPMX 相关的专利（医药）

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项与 PfPMX 相关的文献（医药）

2022-09-01·Journal of Biological Chemistry

The nepenthesin insert in the Plasmodium falciparum aspartic protease plasmepsin V is necessary for enzyme function

Article

作者: Polino, Alexander J ; Bobba, Suhas ; Miller, Justin J ; Goldberg, Daniel E ; Mukherjee, Sumit ; Bowman, Gregory R ; Bhakat, Soumendranath

Plasmepsin V (PM V) is a pepsin-like aspartic protease essential for growth of the malarial parasite Plasmodium falciparum. Previous work has shown PM V to be an endoplasmic reticulum-resident protease that processes parasite proteins destined for export into the host cell. Depletion or inhibition of the enzyme is lethal during asexual replication within red blood cells as well as during the formation of sexual stage gametocytes. The structure of the Plasmodium vivax PM V has been characterized by X-ray crystallography, revealing a canonical pepsin fold punctuated by structural features uncommon to secretory aspartic proteases; however, the function of this unique structure is unclear. Here, we used parasite genetics to probe these structural features by attempting to rescue lethal PM V depletion with various mutant enzymes. We found an unusual nepenthesin 1-type insert in the PM V gene to be essential for parasite growth and PM V activity. Mutagenesis of the nepenthesin insert suggests that both its amino acid sequence and one of the two disulfide bonds that undergird its structure are required for the insert's role in PM V function. Furthermore, molecular dynamics simulations paired with Markov state modeling suggest that mutations to the nepenthesin insert may allosterically affect PM V catalysis through multiple mechanisms. Taken together, these data provide further insights into the structure of the P. falciparum PM V protease.

2022-04-01·Protein Science4区 · 生物学

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

4区 · 生物学

Article

作者: Deshmukh, Anuradha ; Suryawanshi, Abhishek B. ; Wlodawer, Alexander ; Edwards, Thomas E. ; Pahelkar, Nikhil ; Yada, Rickey Y. ; Lorimer, Donald D. ; Gustchina, Alla ; Xiao, Huogen ; Mishra, Vandana ; Labaied, Mehdi ; Kesari, Pooja ; Bhaumik, Prasenjit ; Abendroth, Jan ; Dupuis, John H. ; Rathore, Ishan

AbstractPlasmodium 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 is 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.