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6c4g

From Proteopedia

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Plasmepsin V from Plasmodium vivax bound to a transition state mimetic (WEHI-601)

Structural highlights

6c4g is a 1 chain structure with sequence from Plasmodium vivax. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.39Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PLM5_PLAVS During the asexual blood stage, plays an essential role in the export of several proteins into the host erythrocytes by cleaving the pentameric localization motif RxLxE/Q/D (termed Plasmodium export element (PEXEL)) located downstream of the N-terminal secretory signal sequence (PubMed:24983235). Specifically, cleaves after the leucine residue in the RxLxE/Q/D (or RxLxxE) motif of exported proteins including EMP1 (By similarity). Also, by regulating protein export, plays an essential role in gametocyte development and thus parasite transmission to the mosquito vector (By similarity).[UniProtKB:Q8I6Z5][UniProtKB:W7JPD9]^[1]

Publication Abstract from PubMed

Plasmepsin V is an aspartyl protease that plays a critical role in the export of proteins bearing the Plasmodium export element (PEXEL) motif (RxLxQ/E/D) to the infected host erythrocyte, and thus the survival of the malaria parasite. Previously, development of transition state PEXEL mimetic inhibitors of plasmepsin V have primarily focused on demonstrating the importance of the P3 Arg and P1 Leu in binding affinity and selectivity. Here, we investigate the importance of the P2 position by incorporating both natural and non-natural amino acids into this position and show disubstituted beta-carbon amino acids convey the greatest potency. Consequently, we show analogues with either cyclohexylglycine or phenylglycine in the P2 position are the most potent inhibitors of plasmepsin V that impair processing of the PEXEL motif in exported proteins resulting in death of P. falciparum asexual stage parasites.

Enhanced antimalarial activity of plasmepsin V inhibitors by modification of the P2 position of PEXEL peptidomimetics.,Nguyen W, Hodder AN, de Lezongard RB, Czabotar PE, Jarman KE, O'Neill MT, Thompson JK, Jousset Sabroux H, Cowman AF, Boddey JA, Sleebs BE Eur J Med Chem. 2018 Jun 25;154:182-198. doi: 10.1016/j.ejmech.2018.05.022. Epub , 2018 May 18. PMID:29800827^[2]

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

References

↑ Sleebs BE, Lopaticki S, Marapana DS, O'Neill MT, Rajasekaran P, Gazdik M, Günther S, Whitehead LW, Lowes KN, Barfod L, Hviid L, Shaw PJ, Hodder AN, Smith BJ, Cowman AF, Boddey JA. Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. PLoS Biol. 2014 Jul 1;12(7):e1001897. PMID:24983235 doi:10.1371/journal.pbio.1001897
↑ Nguyen W, Hodder AN, de Lezongard RB, Czabotar PE, Jarman KE, O'Neill MT, Thompson JK, Jousset Sabroux H, Cowman AF, Boddey JA, Sleebs BE. Enhanced antimalarial activity of plasmepsin V inhibitors by modification of the P2 position of PEXEL peptidomimetics. Eur J Med Chem. 2018 Jun 25;154:182-198. doi: 10.1016/j.ejmech.2018.05.022. Epub , 2018 May 18. PMID:29800827 doi:http://dx.doi.org/10.1016/j.ejmech.2018.05.022

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6c4g"

@@ Line 3: / Line 3: @@
 <StructureSection load='6c4g' size='340' side='right'caption='[[6c4g]], [[Resolution|resolution]] 2.39&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6c4g]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Haemamoeba_vivax Haemamoeba vivax]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C4G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C4G FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6c4g]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_vivax Plasmodium vivax]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C4G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6C4G FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EQG:benzyl+[(6S,7S,10S,13S,18Z)-18-amino-10-cyclohexyl-6-hydroxy-18-imino-7-(2-methylpropyl)-4,9,12-trioxo-1-phenyl-16-oxa-3,8,11,17-tetraazaoctadecan-13-yl]carbamate'>EQG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 2.39&#8491;</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=6c4g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c4g OCA], [http://pdbe.org/6c4g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6c4g RCSB], [http://www.ebi.ac.uk/pdbsum/6c4g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6c4g ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EQG:benzyl+[(6S,7S,10S,13S,18Z)-18-amino-10-cyclohexyl-6-hydroxy-18-imino-7-(2-methylpropyl)-4,9,12-trioxo-1-phenyl-16-oxa-3,8,11,17-tetraazaoctadecan-13-yl]carbamate'>EQG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=6c4g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c4g OCA], [https://pdbe.org/6c4g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6c4g RCSB], [https://www.ebi.ac.uk/pdbsum/6c4g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6c4g ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/PLM5_PLAVS PLM5_PLAVS] During the asexual blood stage, plays an essential role in the export of several proteins into the host erythrocytes by cleaving the pentameric localization motif RxLxE/Q/D (termed Plasmodium export element (PEXEL)) located downstream of the N-terminal secretory signal sequence (PubMed:24983235). Specifically, cleaves after the leucine residue in the RxLxE/Q/D (or RxLxxE) motif of exported proteins including EMP1 (By similarity). Also, by regulating protein export, plays an essential role in gametocyte development and thus parasite transmission to the mosquito vector (By similarity).[UniProtKB:Q8I6Z5][UniProtKB:W7JPD9]<ref>PMID:24983235</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Haemamoeba vivax]]
 [[Category: Large Structures]]
-[[Category: Boddey, J A]]
+[[Category: Plasmodium vivax]]
-[[Category: Cowman, A F]]
+[[Category: Boddey JA]]
-[[Category: Czabotar, P E]]
+[[Category: Cowman AF]]
-[[Category: Hodder, A N]]
+[[Category: Czabotar PE]]
-[[Category: Nguyen, W]]
+[[Category: Hodder AN]]
-[[Category: Sleebs, B E]]
+[[Category: Nguyen W]]
-[[Category: Hydrolase]]
+[[Category: Sleebs BE]]
-[[Category: Inhibitor]]
-[[Category: Malaria]]
-[[Category: Plasmepsin]]
-[[Category: Protease]]

6c4g

From Proteopedia

Current revision

Plasmepsin V from Plasmodium vivax bound to a transition state mimetic (WEHI-601)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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