7ry7

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Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7

Structural highlights

7ry7 is a 1 chain structure with sequence from Plasmodium falciparum 3D7. This structure supersedes the now removed PDB entry 6ors. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.1Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PLM10_PLAF7 During the asexual blood stage, processes key proteins essential for merozoite egress and invasion of host erythrocytes (PubMed:29074775, PubMed:32109369). Cleaves and activates proteases SUB1 and SUB2 (PubMed:29074775, PubMed:32109369). May process members of the EBL and Rh protein families (PubMed:32109369). Also cleaves apical membrane protein AMA1 (PubMed:29074775). During the mosquito vector stage and probably in ookinetes, cleaves CelTOS (PubMed:29074775).^[1] ^[2]

Publication Abstract from PubMed

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.

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.,Kesari P, Deshmukh A, Pahelkar N, Suryawanshi AB, Rathore I, Mishra V, Dupuis JH, Xiao H, Gustchina A, Abendroth J, Labaied M, Yada RY, Wlodawer A, Edwards TE, Lorimer DD, Bhaumik P Protein Sci. 2022 Jan 20. doi: 10.1002/pro.4279. PMID:35048450^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Pino P, Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, Collins CR, Blackman MJ, Kursula I, Heussler V, Brochet M, Soldati-Favre D. A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science. 2017 Oct 27;358(6362):522-528. doi: 10.1126/science.aaf8675. PMID:29074775 doi:http://dx.doi.org/10.1126/science.aaf8675
↑ Favuzza P, de Lera Ruiz M, Thompson JK, Triglia T, Ngo A, Steel RWJ, Vavrek M, Christensen J, Healer J, Boyce C, Guo Z, Hu M, Khan T, Murgolo N, Zhao L, Penington JS, Reaksudsan K, Jarman K, Dietrich MH, Richardson L, Guo KY, Lopaticki S, Tham WH, Rottmann M, Papenfuss T, Robbins JA, Boddey JA, Sleebs BE, Sabroux HJ, McCauley JA, Olsen DB, Cowman AF. Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle. Cell Host Microbe. 2020 Apr 8;27(4):642-658.e12. doi: 10.1016/j.chom.2020.02.005., Epub 2020 Feb 27. PMID:32109369 doi:http://dx.doi.org/10.1016/j.chom.2020.02.005
↑ Kesari P, Deshmukh A, Pahelkar N, Suryawanshi AB, Rathore I, Mishra V, Dupuis JH, Xiao H, Gustchina A, Abendroth J, Labaied M, Yada RY, Wlodawer A, Edwards TE, Lorimer DD, Bhaumik P. 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. Protein Sci. 2022 Jan 20. doi: 10.1002/pro.4279. PMID:35048450 doi:http://dx.doi.org/10.1002/pro.4279