1yvb

From Proteopedia

(Difference between revisions)

Current revision

the Plasmodium falciparum Cysteine Protease Falcipain-2

Structural highlights

1yvb is a 2 chain structure with sequence from Gallus gallus and Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FPC2A_PLAF7 Cysteine protease which cleaves native host hemoglobin and globin in the food vacuole during the asexual blood stage (PubMed:10887194, PubMed:15070727, PubMed:15964982, PubMed:16777845, PubMed:19357776, PubMed:25791019). The binding to host hemoglobin is pH-sensitive and only occurs at acidic pH (PubMed:16777845). Cleaves ankyrin and protein 4.1, two components of host erythrocyte membrane cytoskeleton required for the stability of the erythrocyte membrane, and thus may be involved in parasite release (PubMed:11463472). Preferentially cleaves substrates which have an arginine or lysine at the P1 position and a leucine or phenylalanine at the P2 position (PubMed:10887194, PubMed:19357776).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Falcipain-2 (FP2), the major cysteine protease of the human malaria parasite Plasmodium falciparum, is a hemoglobinase and promising drug target. Here we report the crystal structure of FP2 in complex with a protease inhibitor, cystatin. The FP2 structure reveals two previously undescribed cysteine protease structural motifs, designated FP2(nose) and FP2(arm), in addition to details of the active site that will help focus inhibitor design. Unlike most cysteine proteases, FP2 does not require a prodomain but only the short FP2(nose) motif to correctly fold and gain catalytic activity. Our structure and mutagenesis data suggest a molecular basis for this unique mechanism by highlighting the functional role of two Tyr within FP2(nose) and a conserved Glu outside this motif. The FP2(arm) motif is required for hemoglobinase activity. The structure reveals topographic features and a negative charge cluster surrounding FP2(arm) that suggest it may serve as an exo-site for hemoglobin binding. Motifs similar to FP2(nose) and FP2(arm) are found only in related plasmodial proteases, suggesting that they confer malaria-specific functions.

Structural basis for unique mechanisms of folding and hemoglobin binding by a malarial protease.,Wang SX, Pandey KC, Somoza JR, Sijwali PS, Kortemme T, Brinen LS, Fletterick RJ, Rosenthal PJ, McKerrow JH Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11503-8. Epub 2006 Jul 24. PMID:16864794^[8]

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

References

↑ Shenai BR, Sijwali PS, Singh A, Rosenthal PJ. Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum. J Biol Chem. 2000 Sep 15;275(37):29000-10. PMID:10887194 doi:10.1074/jbc.M004459200
↑ Dua M, Raphael P, Sijwali PS, Rosenthal PJ, Hanspal M. Recombinant falcipain-2 cleaves erythrocyte membrane ankyrin and protein 4.1. Mol Biochem Parasitol. 2001 Aug;116(1):95-9. PMID:11463472 doi:10.1016/s0166-6851(01)00306-1
↑ Sijwali PS, Rosenthal PJ. Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4384-9. PMID:15070727 doi:10.1073/pnas.0307720101
↑ Pandey KC, Wang SX, Sijwali PS, Lau AL, McKerrow JH, Rosenthal PJ. The Plasmodium falciparum cysteine protease falcipain-2 captures its substrate, hemoglobin, via a unique motif. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9138-43. PMID:15964982 doi:10.1073/pnas.0502368102
↑ Hogg T, Nagarajan K, Herzberg S, Chen L, Shen X, Jiang H, Wecke M, Blohmke C, Hilgenfeld R, Schmidt CL. Structural and functional characterization of Falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum. J Biol Chem. 2006 Sep 1;281(35):25425-37. Epub 2006 Jun 15. PMID:16777845 doi:10.1074/jbc.M603776200
↑ Subramanian S, Hardt M, Choe Y, Niles RK, Johansen EB, Legac J, Gut J, Kerr ID, Craik CS, Rosenthal PJ. Hemoglobin cleavage site-specificity of the Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3. PLoS One. 2009;4(4):e5156. PMID:19357776 doi:10.1371/journal.pone.0005156
↑ Marques AF, Gomes PS, Oliveira PL, Rosenthal PJ, Pascutti PG, Lima LM. Allosteric regulation of the Plasmodium falciparum cysteine protease falcipain-2 by heme. Arch Biochem Biophys. 2015 May 1;573:92-9. PMID:25791019 doi:10.1016/j.abb.2015.03.007
↑ Wang SX, Pandey KC, Somoza JR, Sijwali PS, Kortemme T, Brinen LS, Fletterick RJ, Rosenthal PJ, McKerrow JH. Structural basis for unique mechanisms of folding and hemoglobin binding by a malarial protease. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11503-8. Epub 2006 Jul 24. PMID:16864794

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1yvb"

Categories: Gallus gallus | Large Structures | Plasmodium falciparum 3D7 | Wang SX

@@ Line 3: / Line 3: @@
 <StructureSection load='1yvb' size='340' side='right'caption='[[1yvb]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1yvb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] and [https://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YVB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1YVB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1yvb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] and [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YVB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1YVB FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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]] 2.7&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1atk|1atk]], [[1pe6|1pe6]], [[1aim|1aim]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AF239801 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</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=1yvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1yvb OCA], [https://pdbe.org/1yvb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1yvb RCSB], [https://www.ebi.ac.uk/pdbsum/1yvb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1yvb ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/CYT_CHICK CYT_CHICK]] This protein binds tightly to and inhibits a variety of thiol proteases including ficin, papain, and cathepsins B, C, H, and L. Although isolated from egg white, it is also present in serum.
+[https://www.uniprot.org/uniprot/FPC2A_PLAF7 FPC2A_PLAF7] Cysteine protease which cleaves native host hemoglobin and globin in the food vacuole during the asexual blood stage (PubMed:10887194, PubMed:15070727, PubMed:15964982, PubMed:16777845, PubMed:19357776, PubMed:25791019). The binding to host hemoglobin is pH-sensitive and only occurs at acidic pH (PubMed:16777845). Cleaves ankyrin and protein 4.1, two components of host erythrocyte membrane cytoskeleton required for the stability of the erythrocyte membrane, and thus may be involved in parasite release (PubMed:11463472). Preferentially cleaves substrates which have an arginine or lysine at the P1 position and a leucine or phenylalanine at the P2 position (PubMed:10887194, PubMed:19357776).<ref>PMID:10887194</ref> <ref>PMID:11463472</ref> <ref>PMID:15070727</ref> <ref>PMID:15964982</ref> <ref>PMID:16777845</ref> <ref>PMID:19357776</ref> <ref>PMID:25791019</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 16: / Line 15: @@
   <jmolCheckbox>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/yv/1yvb_consurf.spt"</scriptWhenChecked>
-    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
@@ Line 30: / Line 29: @@
 </div>
 <div class="pdbe-citations 1yvb" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Proteinase|Proteinase]]
 == References ==
 <references/>
@@ Line 39: / Line 35: @@
 [[Category: Gallus gallus]]
 [[Category: Large Structures]]
-[[Category: Plaf7]]
+[[Category: Plasmodium falciparum 3D7]]
-[[Category: Wang, S X]]
+[[Category: Wang SX]]
-[[Category: Cysteine protease-inhibitor complex]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]

1yvb

From Proteopedia

Current revision

the Plasmodium falciparum Cysteine Protease Falcipain-2

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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