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| | <StructureSection load='6pgr' size='340' side='right'caption='[[6pgr]], [[Resolution|resolution]] 1.95Å' scene=''> | | <StructureSection load='6pgr' size='340' side='right'caption='[[6pgr]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6pgr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PGR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PGR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6pgr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PGR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PGR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8XY:6-bromo-N-(1H-indol-4-yl)-1-benzothiophene-2-carboxamide'>8XY</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]] 1.95Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v15|5v15]], [[5v4j|5v4j]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8XY:6-bromo-N-(1H-indol-4-yl)-1-benzothiophene-2-carboxamide'>8XY</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=6pgr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pgr OCA], [https://pdbe.org/6pgr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pgr RCSB], [https://www.ebi.ac.uk/pdbsum/6pgr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pgr 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=6pgr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pgr OCA], [http://pdbe.org/6pgr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pgr RCSB], [http://www.ebi.ac.uk/pdbsum/6pgr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pgr ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DHYS_HUMAN DHYS_HUMAN]] Catalyzes the NAD-dependent oxidative cleavage of spermidine and the subsequent transfer of the butylamine moiety of spermidine to the epsilon-amino group of a specific lysine residue of the eIF-5A precursor protein to form the intermediate deoxyhypusine residue. | + | [https://www.uniprot.org/uniprot/DHYS_HUMAN DHYS_HUMAN] Catalyzes the NAD-dependent oxidative cleavage of spermidine and the subsequent transfer of the butylamine moiety of spermidine to the epsilon-amino group of a specific lysine residue of the eIF-5A precursor protein to form the intermediate deoxyhypusine residue. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6pgr" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6pgr" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Deoxyhypusine synthase|Deoxyhypusine synthase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Transferase]]
| + | [[Category: Ambrus-Aikelin G]] |
| - | [[Category: Ambrus-Aikelin, G]] | + | [[Category: Klein MG]] |
| - | [[Category: Klein, M G]] | + | |
| - | [[Category: Deoxyhypusine]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Transferase-inhibitor complex]]
| + | |
| Structural highlights
Function
DHYS_HUMAN Catalyzes the NAD-dependent oxidative cleavage of spermidine and the subsequent transfer of the butylamine moiety of spermidine to the epsilon-amino group of a specific lysine residue of the eIF-5A precursor protein to form the intermediate deoxyhypusine residue.
Publication Abstract from PubMed
Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition of DHPS is a promising therapeutic option for the treatment of cancer. To discover novel lead compounds that target DHPS, we conducted synthetic studies with a hit obtained via high-throughput screening. Optimization of the ring structures of the amide compound (2) led to bromobenzothiophene (11g) with potent inhibitory activity against DHPS. X-ray crystallographic analysis of 11g complexed with DHPS revealed a dramatic conformational change in DHPS, which suggests the presence of a novel allosteric site. These findings provide the basis for the development of novel therapy distinct from spermidine mimetic inhibitors.
Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase.,Tanaka Y, Kurasawa O, Yokota A, Klein MG, Ono K, Saito B, Matsumoto S, Okaniwa M, Ambrus-Aikelin G, Morishita D, Kitazawa S, Uchiyama N, Ogawa K, Kimura H, Imamura S J Med Chem. 2020 Mar 26;63(6):3215-3226. doi: 10.1021/acs.jmedchem.9b01979. Epub , 2020 Mar 16. PMID:32142284[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tanaka Y, Kurasawa O, Yokota A, Klein MG, Ono K, Saito B, Matsumoto S, Okaniwa M, Ambrus-Aikelin G, Morishita D, Kitazawa S, Uchiyama N, Ogawa K, Kimura H, Imamura S. Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase. J Med Chem. 2020 Mar 26;63(6):3215-3226. doi: 10.1021/acs.jmedchem.9b01979. Epub , 2020 Mar 16. PMID:32142284 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01979
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