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4zx3

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Revision as of 10:26, 27 September 2017

X-ray crystal structure of PfA-M1 in complex with hydroxamic acid-based inhibitor 10b

Structural highlights

4zx3 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	3ebg, 4zw3, 4zw5, 4zw6, 4zw7, 4zw8, 4zx4, 4zx5, 4zx6
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.

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4zx3"

@@ Line 6: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4TK:N-[(1R)-1-(4-BROMOPHENYL)-2-(HYDROXYAMINO)-2-OXOETHYL]-2,2-DIMETHYLPROPANAMIDE'>4TK</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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">[[3ebg|3ebg]], [[4zw3|4zw3]], [[4zw5|4zw5]], [[4zw6|4zw6]], [[4zw7|4zw7]], [[4zw8|4zw8]], [[4zx4|4zx4]], [[4zx5|4zx5]], [[4zx6|4zx6]]</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=4zx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zx3 OCA], [http://pdbe.org/4zx3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zx3 RCSB], [http://www.ebi.ac.uk/pdbsum/4zx3 PDBsum]</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=4zx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zx3 OCA], [http://pdbe.org/4zx3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zx3 RCSB], [http://www.ebi.ac.uk/pdbsum/4zx3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zx3 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 4zx3" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Aminopeptidase|Aminopeptidase]]
 == References ==
 <references/>

4zx3

From Proteopedia

Revision as of 10:26, 27 September 2017

X-ray crystal structure of PfA-M1 in complex with hydroxamic acid-based inhibitor 10b

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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