4k5n: Difference between revisions

Latest revision as of 15:54, 20 September 2023

Phosphonic Arginine Mimetics as Inhibitors of the M1 Aminopeptidases from Plasmodium falciparum

Structural highlights

4k5n 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 1.91Å
Ligands:	1OU, GOL, MG, ZN
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 malaria parasite Plasmodium falciparum employs two metallo-aminopeptidases, PfA-M1 and PfA-M17, which are essential for parasite survival. Compounds that inhibit the activity of either enzyme represent leads for the development of new anti-malarial drugs. Here we report the synthesis and structure-activity-relationships of a small library of phosphonic acid arginine mimetics that probe the S1 pocket of both enzymes, and map the necessary interactions that would be important for a dual inhibitor.

Synthesis and Structure-Activity Relationships of Phosphonic Arginine Mimetics as Inhibitors of the M1 and M17 Aminopeptidases from Plasmodium falciparum,Kannan Sivaraman K, Paiardini A, Sienczyk M, Ruggeri C, Oellig CA, Dalton JP, Scammells PJ, Drag M, McGowan S J Med Chem. 2013 May 28. PMID:23713488^[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
↑ Kannan Sivaraman K, Paiardini A, Sienczyk M, Ruggeri C, Oellig CA, Dalton JP, Scammells PJ, Drag M, McGowan S. Synthesis and Structure-Activity Relationships of Phosphonic Arginine Mimetics as Inhibitors of the M1 and M17 Aminopeptidases from Plasmodium falciparum J Med Chem. 2013 May 28. PMID:23713488 doi:10.1021/jm4005972

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OCA

[1] 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

[2] 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

[3] Kannan Sivaraman K, Paiardini A, Sienczyk M, Ruggeri C, Oellig CA, Dalton JP, Scammells PJ, Drag M, McGowan S. Synthesis and Structure-Activity Relationships of Phosphonic Arginine Mimetics as Inhibitors of the M1 and M17 Aminopeptidases from Plasmodium falciparum J Med Chem. 2013 May 28. PMID:23713488 doi:10.1021/jm4005972

[1]

[2]

[3]

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4k5n]] 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=4K5N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K5N FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1OU:[(R)-AMINO(4-CARBAMIMIDAMIDOPHENYL)METHYL]PHOSPHONIC+ACID'>1OU</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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.91&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1OU:[(R)-AMINO(4-CARBAMIMIDAMIDOPHENYL)METHYL]PHOSPHONIC+ACID'>1OU</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'>[https://proteopedia.org/fgij/fg.htm?mol=4k5n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k5n OCA], [https://pdbe.org/4k5n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k5n RCSB], [https://www.ebi.ac.uk/pdbsum/4k5n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k5n ProSAT]</span></td></tr>
 </table>

4k5n: Difference between revisions

Latest revision as of 15:54, 20 September 2023

Phosphonic Arginine Mimetics as Inhibitors of the M1 Aminopeptidases from Plasmodium falciparum

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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