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| | <StructureSection load='6p4v' size='340' side='right'caption='[[6p4v]], [[Resolution|resolution]] 1.65Å' scene=''> | | <StructureSection load='6p4v' size='340' side='right'caption='[[6p4v]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6p4v]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P4V OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6P4V FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6p4v]] 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=6P4V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P4V FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GC7:1-GUANIDINIUM-7-AMINOHEPTANE'>GC7</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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]] 1.65Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v2e|5v2e]], [[5v4j|5v4j]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GC7:1-GUANIDINIUM-7-AMINOHEPTANE'>GC7</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DHPS, DS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6p4v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p4v OCA], [https://pdbe.org/6p4v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p4v RCSB], [https://www.ebi.ac.uk/pdbsum/6p4v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p4v ProSAT]</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://proteopedia.org/fgij/fg.htm?mol=6p4v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p4v OCA], [http://pdbe.org/6p4v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p4v RCSB], [http://www.ebi.ac.uk/pdbsum/6p4v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p4v 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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[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: Gc7]]
| + | |
| - | [[Category: Hypusine]]
| + | |
| - | [[Category: Nad cofactor]]
| + | |
| - | [[Category: Spermidine]]
| + | |
| - | [[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.
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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