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| | ==X-ray crystal structure of PfA-M1 in complex with hydroxamic acid-based inhibitor 9b== | | ==X-ray crystal structure of PfA-M1 in complex with hydroxamic acid-based inhibitor 9b== |
| - | <StructureSection load='4zw3' size='340' side='right' caption='[[4zw3]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4zw3' size='340' side='right'caption='[[4zw3]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4zw3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZW3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZW3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4zw3]] is a 1 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=4ZW3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZW3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4S9:TERT-BUTYL+[(1S)-1-(4-BROMOPHENYL)-2-(HYDROXYAMINO)-2-OXOETHYL]CARBAMATE'>4S9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ebg|3ebg]], [[4zw5|4zw5]], [[4zw6|4zw6]], [[4zw7|4zw7]], [[4zw8|4zw8]], [[4zx3|4zx3]], [[4zx4|4zx4]], [[4zx5|4zx5]], [[4zx6|4zx6]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4S9:TERT-BUTYL+[(1S)-1-(4-BROMOPHENYL)-2-(HYDROXYAMINO)-2-OXOETHYL]CARBAMATE'>4S9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=4zw3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zw3 OCA], [http://pdbe.org/4zw3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zw3 RCSB], [http://www.ebi.ac.uk/pdbsum/4zw3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zw3 ProSAT]</span></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=4zw3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zw3 OCA], [https://pdbe.org/4zw3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zw3 RCSB], [https://www.ebi.ac.uk/pdbsum/4zw3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zw3 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AMP1_PLAFQ AMP1_PLAFQ]] Displays aminopeptidase activity with a broad substrate specificity. Preferentially hydrolyzes L-Lys-AMC but also shows strong activity against L-Ala-AMC, L-Arg-AMC and L-Leu-AMC.<ref>PMID:12166515</ref> <ref>PMID:19196988</ref> | + | [https://www.uniprot.org/uniprot/AMP1_PLAFQ AMP1_PLAFQ] Displays aminopeptidase activity with a broad substrate specificity. Preferentially hydrolyzes L-Lys-AMC but also shows strong activity against L-Ala-AMC, L-Arg-AMC and L-Leu-AMC.<ref>PMID:12166515</ref> <ref>PMID:19196988</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Aminopeptidase|Aminopeptidase]] | + | *[[Aminopeptidase 3D structures|Aminopeptidase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Drinkwater, N]] | + | [[Category: Large Structures]] |
| - | [[Category: McGowan, S]] | + | [[Category: Plasmodium falciparum FcB1/Columbia]] |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]] | + | [[Category: Drinkwater N]] |
| - | [[Category: Hydroxamic acid]] | + | [[Category: McGowan S]] |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: M1 alanyl-aminopeptidase]]
| + | |
| - | [[Category: Protease]]
| + | |
| Structural highlights
4zw3 is a 1 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.
| | Method: | X-ray diffraction, Resolution 1.8Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
AMP1_PLAFQ Displays aminopeptidase activity with a broad substrate specificity. Preferentially hydrolyzes L-Lys-AMC but also shows strong activity against L-Ala-AMC, L-Arg-AMC and L-Leu-AMC.[1] [2]
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Allary M, Schrevel J, Florent I. Properties, stage-dependent expression and localization of Plasmodium falciparum M1 family zinc-aminopeptidase. Parasitology. 2002 Jul;125(Pt 1):1-10. PMID:12166515
- ↑ McGowan S, Porter CJ, Lowther J, Stack CM, Golding SJ, Skinner-Adams TS, Trenholme KR, Teuscher F, Donnelly SM, Grembecka J, Mucha A, Kafarski P, Degori R, Buckle AM, Gardiner DL, Whisstock JC, Dalton JP. Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase. Proc Natl Acad Sci U S A. 2009 Feb 5. PMID:19196988
- ↑ 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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