6dft

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<StructureSection load='6dft' size='340' side='right' caption='[[6dft]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
<StructureSection load='6dft' size='340' side='right' caption='[[6dft]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6dft]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DFT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DFT FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6dft]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_(trypanozoon)_brucei Trypanosoma (trypanozoon) brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DFT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DFT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DHSc ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5691 Trypanosoma (Trypanozoon) brucei]), DHSp ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5691 Trypanosoma (Trypanozoon) brucei])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.46 2.5.1.46] </span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.46 2.5.1.46] </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=6dft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dft OCA], [http://pdbe.org/6dft PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dft RCSB], [http://www.ebi.ac.uk/pdbsum/6dft PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dft ProSAT]</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=6dft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dft OCA], [http://pdbe.org/6dft PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dft RCSB], [http://www.ebi.ac.uk/pdbsum/6dft PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dft ProSAT]</span></td></tr>
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Polyamine biosynthesis is a key drug target in African trypanosomes. The "resurrection drug" eflornithine (difluoromethylornithine), which is used clinically to treat human African trypanosomiasis, inhibits the first step in polyamine (spermidine) biosynthesis, a highly regulated pathway in most eukaryotic cells. Previously, we showed that activity of a key trypanosomatid spermidine biosynthetic enzyme, S-adenosylmethionine decarboxylase, is regulated by heterodimer formation with a catalytically dead paralog (a prozyme). Here, we describe an expansion of this prozyme paradigm to the enzyme deoxyhypusine synthase, which is required for spermidine-dependent hypusine modification of a lysine residue in the essential translation factor eIF5A. Trypanosoma brucei encodes two deoxyhypusine synthase paralogs, one that is catalytically functional but grossly impaired, and the other is inactive. Co-expression in Escherichia coli results in heterotetramer formation with a 3000-fold increase in enzyme activity. This functional complex is also present in T. brucei, and conditional knock-out studies indicate that both DHS genes are essential for in vitro growth and infectivity in mice. The recurrent evolution of paralogous, catalytically dead enzyme-based activating mechanisms may be a consequence of the unusual gene expression in the parasites, which lack transcriptional regulation. Our results suggest that this mechanism may be more widely used by trypanosomatids to control enzyme activity and ultimately influence pathogenesis than currently appreciated.
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Trypanosoma brucei is a neglected tropical disease endemic to Africa. The polyamine spermidine is essential for post-translational hypusine modification of eukaryotic initiation factor 5A (eIF5A), which is catalyzed by deoxyhypusine synthase (TbDHS). In trypanosomatids, deoxyhypusine synthase (DHS) activity is dependent on heterotetramer formation between two paralogs, DHSc and DHSp, both with minimal activity on their own due to missing catalytic residues. We determined the X-ray structure of TbDHS showing a single functional shared active site is formed at the DHSc/DHSp heterodimer interface, with deficiencies in one subunit complemented by the other. Each heterodimer contains two NAD(+) binding sites, one housed in the functional catalytic site and the second bound in a remnant dead site that lacks key catalytic residues. Functional analysis of these sites by site-directed mutagenesis identified long-range contributions to the catalytic site from the dead site. Differences between trypanosomatid and human DHS that could be exploited for drug discovery were identified.
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Allosteric activation of trypanosomatid deoxyhypusine synthase by a catalytically dead paralog.,Nguyen S, Jones DC, Wyllie S, Fairlamb AH, Phillips MA J Biol Chem. 2013 May 24;288(21):15256-67. doi: 10.1074/jbc.M113.461137. Epub, 2013 Mar 21. PMID:23525104<ref>PMID:23525104</ref>
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Trypanosomatid Deoxyhypusine Synthase Activity Is Dependent on Shared Active-Site Complementation between Pseudoenzyme Paralogs.,Afanador GA, Tomchick DR, Phillips MA Structure. 2018 Nov 6;26(11):1499-1512.e5. doi: 10.1016/j.str.2018.07.012. Epub, 2018 Sep 6. PMID:30197036<ref>PMID:30197036</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Revision as of 08:35, 21 February 2019

Trypanosoma brucei deoxyhypusine synthase

6dft, resolution 3.50Å

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