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

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

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 1: / Line 1: @@
-[[Image:3fns.jpg|left|thumb|300px|Crystal Strcture of the Plasmepsin, [[3fns]]]]
+<StructureSection load='' size='350' side='right' caption='Plasmepsin II complex with a potential antimalarial drug (PDB entry [[4cku]])' scene='44/441867/Cv/1'>
-{{STRUCTURE_3fns| right| PDB=3fns  |  SCENE= |CAPTION=Plasmepsin dimer witn Zn+2 ions, [[3fns]] }}
+== 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)'''.
-[[Plasmepsin]] (Plm) is a hemoglobin-degrading enzyme produced by the plasmodium parasite.  It is a potential target for anti-malaria drugs.  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).  ProPml II exhibits a large shift between its domains which renders the protease inactive.  The images on the left and right  correspond to one representative Plm structure, ''i.e.'' the Plasmepsin from ''Plasmodium falciparum'' ([[3fns]]).
+*'''Proplasmepsin II''' exhibits a large shift between its domains which renders the protease inactive<ref>PMID:9886289</ref>.
-<br />
+==Relevance ==
-{{TOC limit|limit=2}}
+Plm is a potential target for anti-malaria drugs<ref>PMID:25719272</ref>.
-== 3D Structures of Plasmepsin ==
+== Structural highlights ==
-<br />
+The active site of Plm II contains a <scene name='44/441867/Cv/4'>catalytic dyad of 2 Asp residues which interact with potential antimalarial inhibitor</scene><ref>PMID:24900843</ref>. <scene name='44/441867/Cv/5'>Whole active site</scene>. Water molecules are shown as red spheres.
-<br />
+</StructureSection>
-<br />
+==3D structures of plasmepsin==
-<br />
-<br />
-''Update June 2011''
+Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
+{{#tree:id=OrganizedByTopic|openlevels=0|
-===HAP===
+*Histo-Aspartic Protease
-[[3fns]] – PfHAP  - ''Plasmodium falciparum''<br />
+**[[3fns]], [[3qvc]], [[6kub]], [[6kuc]], [[6kud]] – PfHAP  - ''Plasmodium falciparum''<br />
-[[3fnt]] – PfHAP + inhibitor pepstatin<br />
+**[[3fnt]] – PfHAP + pepstatin<br />
-[[3fnu]] – PfHAP + KNI-10006<br />
+**[[3fnu]], [[3qvi]] – PfHAP + inhibitor<br />
-===Plm I===
+*Plasmepsin I
-[[3qrv]] – PfPlm I residues 117-457<br />
+**[[3qrv]] – PfPlm I residues 117-457<br />
-[[3qs1]] - PfPlm I residues 117-457 + inhibitor
+**[[3qs1]] - PfPlm I residues 117-457 + inhibitor
-===Plm II===
+*Plasmepsin II
-[[1lf4]] – PfPlm II<br />
+**[[1lf4]] – PfPlm II<br />
-[[3f9q]] – PfPlm II (mutant)<br />
+**[[3f9q]] – PfPlm II (mutant)<br />
-[[2r9b]] – PfPlm II + peptide inhibitor<br />
+**[[2r9b]] – PfPlm II + peptide inhibitor<br />
-[[1w6h]], [[2bju]], [[1lf2]], [[1lf3]], [[1lee]], [[2igx]], [[2igy]] – PfPlm II + inhibitor<br />
+**[[1w6h]], [[2bju]], [[1lf2]], [[1lf3]], [[1lee]], [[2igx]], [[2igy]], [[4cku]], [[4y6m]], [[4z22]], [[5yia]], [[5yib]], [[5yic]], [[5yid]], [[5yie]], [[7qyh]] – PfPlm II + inhibitor<br />
-[[1w6i]], [[1xdh]], [[1xe5]], [[1xe6]], [[1me6]], [[1sme]] – PfPlm II + pepstatin derivative<br />
+**[[4ya8]] – PfPlm II (mutant) + inhibitor<br />
-[[1m43]] - PfPlm II (mutant)  + pepstatin derivative<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 />
-===ProPlm II===
+*Plasmepsin IV
-[[1pfz]] - PfProPlm II<br />
+**[[2anl]] – Plm IV + statine derivative – ''Plasmodium malariae''<br />
-[[1miq]] – PvProPlm II – ''Plasmodium vivax''<br />
+**[[1ls5]] - PfPlm IV + pepstatin derivative<br />
-[[1qs8]] - PvPlm  + pepstatin derivative<br />
-===Plm IV===
+*Plasmepsin V or aspartic protease PM5
-[[2anl]] – Plm IV + statine derivative – ''Plasmodium malariae''<br />
+**[[6c4g]] – PvPlm V + inhibitor<br />
-[[1ls5]] - PfPlm IV + pepstatin derivative<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
+**[[1pfz]], [[5bwy]] - PfProPlm II<br />
+**[[1miq]] – PvProPlm II – ''Plasmodium vivax''<br />
+**[[1qs8]], [[5i70]] - PvPlm II + pepstatin derivative<br />
+}}
+== References ==
+<references/>
 [[Category:Topic Page]]