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| | ==structure of plasmepsin II from Plasmodium Falciparum complexed with inhibitor PG394== | | ==structure of plasmepsin II from Plasmodium Falciparum complexed with inhibitor PG394== |
| - | <StructureSection load='4ya8' size='340' side='right' caption='[[4ya8]], [[Resolution|resolution]] 3.30Å' scene=''> | + | <StructureSection load='4ya8' size='340' side='right'caption='[[4ya8]], [[Resolution|resolution]] 3.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ya8]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Plafa Plafa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YA8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YA8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ya8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YA8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YA8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49W:N-[(2S,3S)-3-HYDROXY-1-PHENYL-4-{[2-(PYRIDIN-2-YL)PROPAN-2-YL]AMINO}BUTAN-2-YL]-N,N-DIPROPYL-5-(PYRIDIN-1(2H)-YL)BENZENE-1,3-DICARBOXAMIDE'>49W</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.301Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Plasmepsin_II Plasmepsin II], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.39 3.4.23.39] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49W:N-[(2S,3S)-3-HYDROXY-1-PHENYL-4-{[2-(PYRIDIN-2-YL)PROPAN-2-YL]AMINO}BUTAN-2-YL]-N,N-DIPROPYL-5-(PYRIDIN-1(2H)-YL)BENZENE-1,3-DICARBOXAMIDE'>49W</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ya8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ya8 OCA], [http://pdbe.org/4ya8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ya8 RCSB], [http://www.ebi.ac.uk/pdbsum/4ya8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ya8 ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ya8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ya8 OCA], [https://pdbe.org/4ya8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ya8 RCSB], [https://www.ebi.ac.uk/pdbsum/4ya8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ya8 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/PLM2_PLAFX PLM2_PLAFX] During the asexual blood stage, participates in initial cleavage of native host hemoglobin (Hb) resulting in Hb denaturation (PubMed:8844673, PubMed:11782538, PubMed:15574427). May cleave preferentially denatured hemoglobin that has been cleaved by PMI (PubMed:8844673). Digestion of host Hb is an essential step which provides the parasite with amino acids for protein synthesis, and regulates osmolarity (Probable).<ref>PMID:11782538</ref> <ref>PMID:15574427</ref> <ref>PMID:8844673</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4ya8" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4ya8" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Plasmepsin|Plasmepsin]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Plafa]] | + | [[Category: Large Structures]] |
| - | [[Category: Plasmepsin II]] | + | [[Category: Plasmodium falciparum]] |
| - | [[Category: Jaudzems, K]] | + | [[Category: Jaudzems K]] |
| - | [[Category: Leitans, J]] | + | [[Category: Leitans J]] |
| - | [[Category: Recacha, R]] | + | [[Category: Recacha R]] |
| - | [[Category: Tars, K]] | + | [[Category: Tars K]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Malaria]]
| + | |
| - | [[Category: Plasmepsin ii]]
| + | |
| Structural highlights
Function
PLM2_PLAFX During the asexual blood stage, participates in initial cleavage of native host hemoglobin (Hb) resulting in Hb denaturation (PubMed:8844673, PubMed:11782538, PubMed:15574427). May cleave preferentially denatured hemoglobin that has been cleaved by PMI (PubMed:8844673). Digestion of host Hb is an essential step which provides the parasite with amino acids for protein synthesis, and regulates osmolarity (Probable).[1] [2] [3]
Publication Abstract from PubMed
Plasmepsin II (PMII) is one of the ten plasmepsins (PMs) identified in the genome of Plasmodium falciparum, the causative agent of the most severe and deadliest form of malaria. Owing to the emergence of P. falciparum strains that are resistant to current antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is a constant pressure to find new and lasting chemotherapeutic drug therapies. Previously, the crystal structure of PMII in complex with NU655, a potent antimalarial hydroxyethylamine-based inhibitor, and the design of new compounds based on it have been reported. In the current study, two of these newly designed hydroxyethylamine-based inhibitors, PG418 and PG394, were cocrystallized with PMII and their structures were solved, analyzed and compared with that of the PMII-NU655 complex. Structural analysis of the PMII-PG418 complex revealed that the flap loop can adopt a fully closed conformation, stabilized by interactions with the inhibitor, and a fully open conformation, causing an overall expansion in the active-site cavity, which in turn causes unstable binding of the inhibitor. PG418 also stabilizes the flexible loop Gln275-Met286 of another monomer in the asymmetric unit of PMII, which is disordered in the PMII-NU655 complex structure. The crystal structure of PMII in complex with the inhibitor PG418 demonstrates the conformational flexibility of the active-site cavity of the plasmepsins. The interactions of the different moieties in the P1' position of PG418 and PG394 with Thr217 have to be taken into account in the design of new potent plasmepsin inhibitors.
Structures of plasmepsin II from Plasmodium falciparum in complex with two hydroxyethylamine-based inhibitors.,Recacha R, Leitans J, Akopjana I, Aprupe L, Trapencieris P, Jaudzems K, Jirgensons A, Tars K Acta Crystallogr F Struct Biol Commun. 2015 Dec 1;71(Pt 12):1531-9. doi:, 10.1107/S2053230X15022049. Epub 2015 Nov 27. PMID:26625296[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Banerjee R, Liu J, Beatty W, Pelosof L, Klemba M, Goldberg DE. Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):990-5. doi: 10.1073/pnas.022630099., Epub 2002 Jan 8. PMID:11782538 doi:http://dx.doi.org/10.1073/pnas.022630099
- ↑ Istvan ES, Goldberg DE. Distal substrate interactions enhance plasmepsin activity. J Biol Chem. 2005 Feb 25;280(8):6890-6. doi: 10.1074/jbc.M412086200. Epub 2004, Dec 1. PMID:15574427 doi:http://dx.doi.org/10.1074/jbc.M412086200
- ↑ Luker KE, Francis SE, Gluzman IY, Goldberg DE. Kinetic analysis of plasmepsins I and II aspartic proteases of the Plasmodium falciparum digestive vacuole. Mol Biochem Parasitol. 1996 Jul;79(1):71-8. doi: 10.1016/0166-6851(96)02651-5. PMID:8844673 doi:http://dx.doi.org/10.1016/0166-6851(96)02651-5
- ↑ Recacha R, Leitans J, Akopjana I, Aprupe L, Trapencieris P, Jaudzems K, Jirgensons A, Tars K. Structures of plasmepsin II from Plasmodium falciparum in complex with two hydroxyethylamine-based inhibitors. Acta Crystallogr F Struct Biol Commun. 2015 Dec 1;71(Pt 12):1531-9. doi:, 10.1107/S2053230X15022049. Epub 2015 Nov 27. PMID:26625296 doi:http://dx.doi.org/10.1107/S2053230X15022049
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