Plasmepsin: Difference between revisions

Latest revision as of 12:50, 31 August 2023

Function

Plasmepsin (Plm) is a hemoglobin-degrading enzyme produced by the plasmodium parasite. It is an aspartic acid protease having 2 aspartic acid residues in the active site. Ten Plm isoforms are known which are named Plm I, II, etc and Histo-Aspartic Protease (HAP).

Proplasmepsin II exhibits a large shift between its domains which renders the protease inactive^[1].

Relevance

Plm is a potential target for anti-malaria drugs^[2].

Structural highlights

The active site of Plm II contains a ^[3]. . Water molecules are shown as red spheres.

Plasmepsin II complex with a potential antimalarial drug (PDB entry 4cku)

Drag the structure with the mouse to rotate

3D structures of plasmepsin3D structures of plasmepsin

Updated on 31-August-2023

ReferencesReferences

↑ Bernstein NK, Cherney MM, Loetscher H, Ridley RG, James MN. Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum. Nat Struct Biol. 1999 Jan;6(1):32-7. PMID:9886289 doi:10.1038/4905
↑ Huizing AP, Mondal M, Hirsch AK. Fighting malaria: structure-guided discovery of nonpeptidomimetic plasmepsin inhibitors. J Med Chem. 2015 Jul 9;58(13):5151-63. doi: 10.1021/jm5014133. Epub 2015 Mar 17. PMID:25719272 doi:http://dx.doi.org/10.1021/jm5014133
↑ Jaudzems K, Tars K, Maurops G, Ivdra N, Otikovs M, Leitans J, Kanepe-Lapsa I, Domraceva I, Mutule I, Trapencieris P, Blackman MJ, Jirgensons A. Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit. ACS Med Chem Lett. 2014 Jan 13;5(4):373-7. doi: 10.1021/ml4004952. eCollection, 2014 Apr 10. PMID:24900843 doi:http://dx.doi.org/10.1021/ml4004952

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Alexander Berchansky, Michal Harel, Jaime Prilusky, Joel L. Sussman

[1] Bernstein NK, Cherney MM, Loetscher H, Ridley RG, James MN. Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum. Nat Struct Biol. 1999 Jan;6(1):32-7. PMID:9886289 doi:10.1038/4905

[2] Huizing AP, Mondal M, Hirsch AK. Fighting malaria: structure-guided discovery of nonpeptidomimetic plasmepsin inhibitors. J Med Chem. 2015 Jul 9;58(13):5151-63. doi: 10.1021/jm5014133. Epub 2015 Mar 17. PMID:25719272 doi:http://dx.doi.org/10.1021/jm5014133

[3] Jaudzems K, Tars K, Maurops G, Ivdra N, Otikovs M, Leitans J, Kanepe-Lapsa I, Domraceva I, Mutule I, Trapencieris P, Blackman MJ, Jirgensons A. Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit. ACS Med Chem Lett. 2014 Jan 13;5(4):373-7. doi: 10.1021/ml4004952. eCollection, 2014 Apr 10. PMID:24900843 doi:http://dx.doi.org/10.1021/ml4004952

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@@ Line 32: / Line 32: @@
 **[[3f9q]] – PfPlm II (mutant)<br />
 **[[2r9b]] – PfPlm II + peptide inhibitor<br />
-**[[1w6h]], [[2bju]], [[1lf2]], [[1lf3]], [[1lee]], [[2igx]], [[2igy]], [[4cku]], [[4y6m]], [[4z22]], [[5yia]], [[5yib]], [[5yic]], [[5yid]], [[5yie]] – PfPlm II + inhibitor<br />
+**[[1w6h]], [[2bju]], [[1lf2]], [[1lf3]], [[1lee]], [[2igx]], [[2igy]], [[4cku]], [[4y6m]], [[4z22]], [[5yia]], [[5yib]], [[5yic]], [[5yid]], [[5yie]], [[7qyh]] – PfPlm II + inhibitor<br />
 **[[4ya8]] – PfPlm II (mutant) + inhibitor<br />
+**[[7ve0]], [[7ve2]] – PfPlm II + drug<br />
 **[[1w6i]], [[1xdh]], [[1xe5]], [[1xe6]], [[1me6]], [[1sme]] – PfPlm II + pepstatin derivative<br />
 **[[1m43]] - PfPlm II (mutant)  + pepstatin derivative<br />
@@ Line 45: / Line 46: @@
 **[[6c4g]] – PvPlm V + inhibitor<br />
+**[[4zl4]] – PvPlm V + transition state analog<br />
 *Plasmepsin X
 **[[7ry7]] – PvPlm X <br />
+**[[7tbc]], [[7tbd]], [[7tbe]], [[8dsr]] – PfPlm X + inhibitor<br />
+**[[7tbb]] – PfPlm X <br />
 *Proplasmepsin II