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[[Image: | ==X-ray crystal structure of the aspartic protease plasmepsin 4 from the malarial parasite plasmodium malariae bound to an allophenylnorstatine based inhibitor== | ||
<StructureSection load='2anl' size='340' side='right' caption='[[2anl]], [[Resolution|resolution]] 3.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2anl]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Plasmodium_malariae Plasmodium malariae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ANL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ANL FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JE2:(4R)-3-{(2S,3S)-2-HYDROXY-3-[(3-HYDROXY-2-METHYLBENZOYL)AMINO]-4-PHENYLBUTANOYL}-5,5-DIMETHYL-N-(2-METHYLBENZYL)-1,3-THIAZOLIDINE-4-CARBOXAMIDE'>JE2</scene><br> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2anl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2anl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2anl RCSB], [http://www.ebi.ac.uk/pdbsum/2anl PDBsum]</span></td></tr> | |||
<table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/an/2anl_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The malarial parasite continues to be one of the leading causes of death in many developing countries. With the development of resistance to the currently available treatments, the discovery of new therapeutics is imperative. Currently, the plasmepsin enzymes found in the food vacuole of the parasite are a chief target for drug development. Allophenylnorstatine-based compounds originally designed to inhibit HIV-1 protease have shown efficacy against all four plasmepsin enzymes found in the food vacuole of Plasmodium falciparum. In this study, the first crystal structure of P. malariae plasmepsin 4 (PmPM4) bound to the allophenylnorstatine-based compound KNI-764 is described at 3.3 Angstroms resolution. The PmPM4-inhibitor complex crystallized in the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 95.9, b = 112.6, c = 90.4 Angstroms, with two molecules in the asymmetric unit related by a non-crystallographic symmetry operator. The structure was refined to a final R factor of 24.7%. The complex showed the inhibitor in an unexpected binding orientation with allophenylnorstatine occupying the S1' pocket. The P2 group was found outside the S2 pocket, wedged between the flap and a juxtaposed loop. Inhibition analysis of PmPM4 also suggests the potential for allophenylnorstatine-based compounds to be effective against all species of malaria infecting humans and for the future development of a broad-based inhibitor. | |||
Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor.,Clemente JC, Govindasamy L, Madabushi A, Fisher SZ, Moose RE, Yowell CA, Hidaka K, Kimura T, Hayashi Y, Kiso Y, Agbandje-McKenna M, Dame JB, Dunn BM, McKenna R Acta Crystallogr D Biol Crystallogr. 2006 Mar;62(Pt 3):246-52. Epub 2006, Feb 22. PMID:16510971<ref>PMID:16510971</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Plasmepsin|Plasmepsin]] | *[[Plasmepsin|Plasmepsin]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Plasmodium malariae]] | [[Category: Plasmodium malariae]] | ||
[[Category: Agbandje-McKenna, M.]] | [[Category: Agbandje-McKenna, M.]] | ||
Revision as of 06:53, 29 September 2014
X-ray crystal structure of the aspartic protease plasmepsin 4 from the malarial parasite plasmodium malariae bound to an allophenylnorstatine based inhibitorX-ray crystal structure of the aspartic protease plasmepsin 4 from the malarial parasite plasmodium malariae bound to an allophenylnorstatine based inhibitor
Structural highlights
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 PubMedThe malarial parasite continues to be one of the leading causes of death in many developing countries. With the development of resistance to the currently available treatments, the discovery of new therapeutics is imperative. Currently, the plasmepsin enzymes found in the food vacuole of the parasite are a chief target for drug development. Allophenylnorstatine-based compounds originally designed to inhibit HIV-1 protease have shown efficacy against all four plasmepsin enzymes found in the food vacuole of Plasmodium falciparum. In this study, the first crystal structure of P. malariae plasmepsin 4 (PmPM4) bound to the allophenylnorstatine-based compound KNI-764 is described at 3.3 Angstroms resolution. The PmPM4-inhibitor complex crystallized in the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 95.9, b = 112.6, c = 90.4 Angstroms, with two molecules in the asymmetric unit related by a non-crystallographic symmetry operator. The structure was refined to a final R factor of 24.7%. The complex showed the inhibitor in an unexpected binding orientation with allophenylnorstatine occupying the S1' pocket. The P2 group was found outside the S2 pocket, wedged between the flap and a juxtaposed loop. Inhibition analysis of PmPM4 also suggests the potential for allophenylnorstatine-based compounds to be effective against all species of malaria infecting humans and for the future development of a broad-based inhibitor. Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor.,Clemente JC, Govindasamy L, Madabushi A, Fisher SZ, Moose RE, Yowell CA, Hidaka K, Kimura T, Hayashi Y, Kiso Y, Agbandje-McKenna M, Dame JB, Dunn BM, McKenna R Acta Crystallogr D Biol Crystallogr. 2006 Mar;62(Pt 3):246-52. Epub 2006, Feb 22. PMID:16510971[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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