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| | <StructureSection load='4zy1' size='340' side='right'caption='[[4zy1]], [[Resolution|resolution]] 2.50Å' scene=''> | | <StructureSection load='4zy1' size='340' side='right'caption='[[4zy1]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4zy1]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Plafq Plafq]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZY1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZY1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4zy1]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_FcB1/Columbia Plasmodium falciparum FcB1/Columbia]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZY1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZY1 FirstGlance]. <br> |
| - | </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=4U5:N-{(1R)-2-(HYDROXYAMINO)-1-[4-(1-METHYL-1H-PYRAZOL-4-YL)PHENYL]-2-OXOETHYL}-2,2-DIMETHYLPROPANAMIDE'>4U5</scene>, <scene name='pdbligand=CO3:CARBONATE+ION'>CO3</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><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=4U5:N-{(1R)-2-(HYDROXYAMINO)-1-[4-(1-METHYL-1H-PYRAZOL-4-YL)PHENYL]-2-OXOETHYL}-2,2-DIMETHYLPROPANAMIDE'>4U5</scene>, <scene name='pdbligand=CO3:CARBONATE+ION'>CO3</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3kqz|3kqz]], [[4zx8|4zx8]], [[4zx9|4zx9]], [[4zy0|4zy0]], [[4zy2|4zy2]], [[4zyq|4zyq]]</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=4zy1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zy1 OCA], [https://pdbe.org/4zy1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zy1 RCSB], [https://www.ebi.ac.uk/pdbsum/4zy1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zy1 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leucyl_aminopeptidase Leucyl aminopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.11.1 3.4.11.1] </span></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=4zy1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zy1 OCA], [http://pdbe.org/4zy1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zy1 RCSB], [http://www.ebi.ac.uk/pdbsum/4zy1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zy1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/A0A024V0B1_PLAFA A0A024V0B1_PLAFA] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Leucyl aminopeptidase]] | + | [[Category: Plasmodium falciparum FcB1/Columbia]] |
| - | [[Category: Plafq]]
| + | [[Category: Drinkwater N]] |
| - | [[Category: Drinkwater, N]] | + | [[Category: McGowan S]] |
| - | [[Category: McGowan, S]] | + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Hydroxamic acid]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: M17 leucyl-aminopeptidase]]
| + | |
| - | [[Category: Protease]]
| + | |
| Structural highlights
4zy1 is a 12 chain structure with sequence from Plasmodium falciparum FcB1/Columbia. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
A0A024V0B1_PLAFA
Publication Abstract from PubMed
Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics.
Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions.,Drinkwater N, Vinh NB, Mistry SN, Bamert RS, Ruggeri C, Holleran JP, Loganathan S, Paiardini A, Charman SA, Powell AK, Avery VM, McGowan S, Scammells PJ Eur J Med Chem. 2016 Mar 3;110:43-64. doi: 10.1016/j.ejmech.2016.01.015. Epub, 2016 Jan 13. PMID:26807544[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Drinkwater N, Vinh NB, Mistry SN, Bamert RS, Ruggeri C, Holleran JP, Loganathan S, Paiardini A, Charman SA, Powell AK, Avery VM, McGowan S, Scammells PJ. Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions. Eur J Med Chem. 2016 Mar 3;110:43-64. doi: 10.1016/j.ejmech.2016.01.015. Epub, 2016 Jan 13. PMID:26807544 doi:http://dx.doi.org/10.1016/j.ejmech.2016.01.015
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