Plasmepsin

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{{STRUCTURE_3fns| right| PDB=3fns | SCENE= |CAPTION=Plasmepsin dimer witn Zn+2 ions, [[3fns]] }}
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<StructureSection load='' size='350' side='right' caption='Plasmepsin II complex with a potential antimalarial drug (PDB entry [[4cku]])' scene='44/441867/Cv/1'>
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[[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]]).
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== Function ==
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[[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)'''.
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<br />
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*'''Proplasmepsin II''' exhibits a large shift between its domains which renders the protease inactive<ref>PMID:9886289</ref>.
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{{TOC limit|limit=2}}
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== 3D Structures of Plasmepsin ==
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==Relevance ==
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Plm is a potential target for anti-malaria drugs<ref>PMID:25719272</ref>.
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Updated: {{REVISIONDAY2}}-{{REVISIONMONTH}}-{{REVISIONYEAR}} (DD-MM-YYYY)
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== Structural highlights ==
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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.
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</StructureSection>
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==3D structures of plasmepsin==
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===HAP===
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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{{#tree:id=OrganizedByTopic|openlevels=0|
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[[3fns]] – PfHAP - ''Plasmodium falciparum''<br />
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*Histo-Aspartic Protease
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[[3fnt]] – PfHAP + inhibitor pepstatin<br />
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[[3fnu]] – PfHAP + KNI-10006<br />
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===Plm I===
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**[[3fns]], [[3qvc]], [[6kub]], [[6kuc]], [[6kud]] – PfHAP - ''Plasmodium falciparum''<br />
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**[[3fnt]] – PfHAP + pepstatin<br />
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**[[3fnu]], [[3qvi]] – PfHAP + inhibitor<br />
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[[3qrv]] – PfPlm I residues 117-457<br />
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*Plasmepsin I
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[[3qs1]] - PfPlm I residues 117-457 + inhibitor
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===Plm II===
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**[[3qrv]] – PfPlm I residues 117-457<br />
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**[[3qs1]] - PfPlm I residues 117-457 + inhibitor
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[[1lf4]] – PfPlm II<br />
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*Plasmepsin II
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[[3f9q]] – PfPlm II (mutant)<br />
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[[2r9b]] – PfPlm II + peptide inhibitor<br />
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[[1w6h]], [[2bju]], [[1lf2]], [[1lf3]], [[1lee]], [[2igx]], [[2igy]] – PfPlm II + inhibitor<br />
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[[1w6i]], [[1xdh]], [[1xe5]], [[1xe6]], [[1me6]], [[1sme]] – PfPlm II + pepstatin derivative<br />
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[[1m43]] - PfPlm II (mutant) + pepstatin derivative<br />
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===ProPlm II===
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**[[1lf4]] – PfPlm II<br />
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**[[3f9q]] – PfPlm II (mutant)<br />
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**[[2r9b]] – PfPlm II + peptide inhibitor<br />
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**[[1w6h]], [[2bju]], [[1lf2]], [[1lf3]], [[1lee]], [[2igx]], [[2igy]], [[4cku]], [[4y6m]], [[4z22]], [[5yia]], [[5yib]], [[5yic]], [[5yid]], [[5yie]], [[7qyh]] – PfPlm II + inhibitor<br />
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**[[4ya8]] – PfPlm II (mutant) + inhibitor<br />
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**[[7ve0]], [[7ve2]] – PfPlm II + drug<br />
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**[[1w6i]], [[1xdh]], [[1xe5]], [[1xe6]], [[1me6]], [[1sme]] – PfPlm II + pepstatin derivative<br />
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**[[1m43]] - PfPlm II (mutant) + pepstatin derivative<br />
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[[1pfz]] - PfProPlm II<br />
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*Plasmepsin IV
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[[1miq]] – PvProPlm II – ''Plasmodium vivax''<br />
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[[1qs8]] - PvPlm + pepstatin derivative<br />
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===Plm IV===
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**[[2anl]] – Plm IV + statine derivative – ''Plasmodium malariae''<br />
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**[[1ls5]] - PfPlm IV + pepstatin derivative<br />
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[[2anl]] – Plm IV + statine derivative – ''Plasmodium malariae''<br />
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*Plasmepsin V or aspartic protease PM5
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[[1ls5]] - PfPlm IV + pepstatin derivative<br />
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**[[6c4g]] – PvPlm V + inhibitor<br />
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**[[4zl4]] – PvPlm V + transition state analog<br />
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*Plasmepsin X
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**[[7ry7]] – PvPlm X <br />
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**[[7tbc]], [[7tbd]], [[7tbe]], [[8dsr]] – PfPlm X + inhibitor<br />
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**[[7tbb]] – PfPlm X <br />
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*Proplasmepsin II
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**[[1pfz]], [[5bwy]] - PfProPlm II<br />
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**[[1miq]] – PvProPlm II – ''Plasmodium vivax''<br />
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**[[1qs8]], [[5i70]] - PvPlm II + pepstatin derivative<br />
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}}
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== References ==
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<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]

Current revision

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

Drag the structure with the mouse to rotate

3D structures of plasmepsin

Updated on 31-August-2023

References

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

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