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6eee

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==X-ray crystal structure of Pf-M17 in complex with inhibitor (6k) and regulatory zinc ion==
==X-ray crystal structure of Pf-M17 in complex with inhibitor (6k) and regulatory zinc ion==
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<StructureSection load='6eee' size='340' side='right' caption='[[6eee]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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<StructureSection load='6eee' size='340' side='right'caption='[[6eee]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6eee]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EEE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EEE FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6eee]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_HB3 Plasmodium falciparum HB3]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EEE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EEE FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=CO3:CARBONATE+ION'>CO3</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=J4V:(1R,2r,3S,5R,7R)-N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)ethyl]tricyclo[3.3.1.1~3,7~]decane-2-carboxamide'>J4V</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
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<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=6eee FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eee OCA], [http://pdbe.org/6eee PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6eee RCSB], [http://www.ebi.ac.uk/pdbsum/6eee PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6eee ProSAT]</span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=CO3:CARBONATE+ION'>CO3</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=J4V:(1R,2r,3S,5R,7R)-N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)ethyl]tricyclo[3.3.1.1~3,7~]decane-2-carboxamide'>J4V</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6eee FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eee OCA], [https://pdbe.org/6eee PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eee RCSB], [https://www.ebi.ac.uk/pdbsum/6eee PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eee ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/A0A0L7KHE6_PLAFX A0A0L7KHE6_PLAFX]
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There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium haemoglobin digestion, and are validated drug targets. We used a multi-target strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum (Pf-M1 and Pf-M17) and P. vivax (Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterisation by co-crystallisation showed that selected compounds utilise new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.
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Hydroxamic acid inhibitors provide cross-species inhibition of Plasmodium M1 and M17 aminopeptidases.,Vinh NB, Drinkwater N, Malcolm TR, Kassiou M, Lucantoni L, Grin PM, Butler GS, Duffy S, Overall CM, Avery VM, Scammells PJ, McGowan S J Med Chem. 2018 Dec 11. doi: 10.1021/acs.jmedchem.8b01310. PMID:30537832<ref>PMID:30537832</ref>
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==See Also==
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*[[Aminopeptidase 3D structures|Aminopeptidase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6eee" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Drinkwater, N]]
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[[Category: Large Structures]]
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[[Category: McGowan, S]]
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[[Category: Plasmodium falciparum HB3]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Drinkwater N]]
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[[Category: Hydroxamic acid]]
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[[Category: McGowan S]]
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[[Category: Inhibitor]]
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[[Category: M17 leucyl-aminopeptidase]]
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[[Category: Protease]]
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Current revision

X-ray crystal structure of Pf-M17 in complex with inhibitor (6k) and regulatory zinc ion

PDB ID 6eee

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