4zqt

From Proteopedia

(Difference between revisions)

Revision as of 12:21, 6 November 2017

Crystal structure of PfA-M1 with virtual ligand inhibitor

Structural highlights

4zqt is a 1 chain structure with sequence from Plaf7. 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

[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

The Plasmodium falciparum PfA-M1 and PfA-M17 metalloaminopeptidases are validated drug targets for the discovery of antimalarial agents. In order to identify dual inhibitors of both proteins, we developed a hierarchical virtual screening approach, followed by in vitro evaluation of the highest scoring hits. Starting from the ZINC database of purchasable compounds, sequential 3D-pharmacophore and molecular docking steps were applied to filter the virtual 'hits'. At the end of virtual screening, 12 compounds were chosen and tested against the in vitro aminopeptidase activity of both PfA-M1 and PfA-M17. Two molecules showed significant inhibitory activity (low micromolar/nanomolar range) against both proteins. Finally, the crystal structure of the most potent compound in complex with both PfA-M1 and PfA-M17 was solved, revealing the binding mode and validating our computational approach.

Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening.,Ruggeri C, Drinkwater N, Sivaraman KK, Bamert RS, McGowan S, Paiardini A PLoS One. 2015 Sep 25;10(9):e0138957. doi: 10.1371/journal.pone.0138957., eCollection 2015. PMID:26406322^[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
↑ Ruggeri C, Drinkwater N, Sivaraman KK, Bamert RS, McGowan S, Paiardini A. Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening. PLoS One. 2015 Sep 25;10(9):e0138957. doi: 10.1371/journal.pone.0138957., eCollection 2015. PMID:26406322 doi:http://dx.doi.org/10.1371/journal.pone.0138957

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 1: / Line 1: @@
 ==Crystal structure of PfA-M1 with virtual ligand inhibitor==
 <StructureSection load='4zqt' size='340' side='right' caption='[[4zqt]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4zqt]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZQT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZQT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4zqt]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZQT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZQT FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4QP:(2R)-2-{[(R)-[(R)-AMINO(PHENYL)METHYL](HYDROXY)PHOSPHORYL]METHYL}-4-METHYLPENTANOIC+ACID'>4QP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=4zqt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zqt OCA], [http://pdbe.org/4zqt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zqt RCSB], [http://www.ebi.ac.uk/pdbsum/4zqt 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=4zqt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zqt OCA], [http://pdbe.org/4zqt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zqt RCSB], [http://www.ebi.ac.uk/pdbsum/4zqt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zqt ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 21: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Plaf7]]
 [[Category: Drinkwater, N]]
 [[Category: McGowan, S]]

4zqt

From Proteopedia

Revision as of 12:21, 6 November 2017

Crystal structure of PfA-M1 with virtual ligand inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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