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==Crystal Structure of Plasmodium Falciparum Spermidine Synthase in Complex with DECARBOXYLATED S-ADENOSYLMETHIONINE5' AND 4- METHYLANILINE== | |||
<StructureSection load='4bp3' size='340' side='right'caption='[[4bp3]], [[Resolution|resolution]] 1.75Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4bp3]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BP3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BP3 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PG:2-(2-{2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHANOL'>1PG</scene>, <scene name='pdbligand=4MN:4-METHYLANILINE'>4MN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=S4M:5-[(S)-(3-AMINOPROPYL)(METHYL)-LAMBDA~4~-SULFANYL]-5-DEOXYADENOSINE'>S4M</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=4bp3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bp3 OCA], [https://pdbe.org/4bp3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bp3 RCSB], [https://www.ebi.ac.uk/pdbsum/4bp3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bp3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q8II73_PLAF7 Q8II73_PLAF7] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The enzymes of the polyamine-biosynthesis pathway have been proposed to be promising drug targets in the treatment of malaria. Spermidine synthase (SpdS; putrescine aminopropyltransferase) catalyzes the transfer of the aminopropyl moiety from decarboxylated S-adenosylmethionine to putrescine, leading to the formation of spermidine and 5'-methylthioadenosine (MTA). In this work, X-ray crystallography was used to examine ligand complexes of SpdS from the malaria parasite Plasmodium falciparum (PfSpdS). Five crystal structures were determined of PfSpdS in complex with MTA and the substrate putrescine, with MTA and spermidine, which was obtained as a result of the enzymatic reaction taking place within the crystals, with dcAdoMet and the inhibitor 4-methylaniline, with MTA and 4-aminomethylaniline, and with a compound predicted in earlier in silico screening to bind to the active site of the enzyme, benzimidazol-(2-yl)pentan-1-amine (BIPA). In contrast to the other inhibitors tested, the complex with BIPA was obtained without any ligand bound to the dcAdoMet-binding site of the enzyme. The complexes with the aniline compounds and BIPA revealed a new mode of ligand binding to PfSpdS. The observed binding mode of the ligands, and the interplay between the two substrate-binding sites and the flexible gatekeeper loop, can be used in the design of new approaches in the search for new inhibitors of SpdS. | |||
Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design.,Sprenger J, Svensson B, Halander J, Carey J, Persson L, Al-Karadaghi S Acta Crystallogr D Biol Crystallogr. 2015 Mar 1;71(Pt 3):484-93. doi:, 10.1107/S1399004714027011. Epub 2015 Feb 26. PMID:25760598<ref>PMID:25760598</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4bp3" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Spermidine synthase 3D structures|Spermidine synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Plasmodium falciparum 3D7]] | |||
[[Category: Al-Karadaghi S]] | |||
[[Category: Halander JC]] | |||
[[Category: Persson L]] | |||
[[Category: Sprenger J]] | |||
[[Category: Svensson B]] | |||
Latest revision as of 14:56, 20 December 2023
Crystal Structure of Plasmodium Falciparum Spermidine Synthase in Complex with DECARBOXYLATED S-ADENOSYLMETHIONINE5' AND 4- METHYLANILINECrystal Structure of Plasmodium Falciparum Spermidine Synthase in Complex with DECARBOXYLATED S-ADENOSYLMETHIONINE5' AND 4- METHYLANILINE
Structural highlights
FunctionPublication Abstract from PubMedThe enzymes of the polyamine-biosynthesis pathway have been proposed to be promising drug targets in the treatment of malaria. Spermidine synthase (SpdS; putrescine aminopropyltransferase) catalyzes the transfer of the aminopropyl moiety from decarboxylated S-adenosylmethionine to putrescine, leading to the formation of spermidine and 5'-methylthioadenosine (MTA). In this work, X-ray crystallography was used to examine ligand complexes of SpdS from the malaria parasite Plasmodium falciparum (PfSpdS). Five crystal structures were determined of PfSpdS in complex with MTA and the substrate putrescine, with MTA and spermidine, which was obtained as a result of the enzymatic reaction taking place within the crystals, with dcAdoMet and the inhibitor 4-methylaniline, with MTA and 4-aminomethylaniline, and with a compound predicted in earlier in silico screening to bind to the active site of the enzyme, benzimidazol-(2-yl)pentan-1-amine (BIPA). In contrast to the other inhibitors tested, the complex with BIPA was obtained without any ligand bound to the dcAdoMet-binding site of the enzyme. The complexes with the aniline compounds and BIPA revealed a new mode of ligand binding to PfSpdS. The observed binding mode of the ligands, and the interplay between the two substrate-binding sites and the flexible gatekeeper loop, can be used in the design of new approaches in the search for new inhibitors of SpdS. Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design.,Sprenger J, Svensson B, Halander J, Carey J, Persson L, Al-Karadaghi S Acta Crystallogr D Biol Crystallogr. 2015 Mar 1;71(Pt 3):484-93. doi:, 10.1107/S1399004714027011. Epub 2015 Feb 26. PMID:25760598[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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