6pgr: Difference between revisions

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~~'''Unreleased structure'''~~

~~The entry~~ 6pgr is ~~ON HOLD~~

==Cocomplex structure of Deoxyhypusine synthase with inhibitor 6-BROMO-N-(1H-INDOL-4-YL)-1-BENZOTHIOPHENE-2-CARBOXAMIDE==

== Structural highlights ==

<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='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='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='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>

</table>

== Function ==

[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.

== 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.

~~Authors:~~ Klein, M~~.G.~~, Ambrus-Aikelin, G.

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<ref>PMID:32142284</ref>

~~Description~~: ~~Cocomplex structure of~~ Deoxyhypusine synthase ~~with inhibitor 6-BROMO-N-(1H-INDOL-4-YL)-1-BENZOTHIOPHENE-2-CARBOXAMIDE~~

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased~~ Structures]]

</div>

[[Category: Ambrus-Aikelin, G]]

[[Category: Klein~~, M.G~~]]

==See Also==

*[[Deoxyhypusine synthase|Deoxyhypusine synthase]]

== References ==

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Ambrus-Aikelin G]]

[[Category: Klein MG]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6pgr is ON HOLD
+==Cocomplex structure of Deoxyhypusine synthase with inhibitor 6-BROMO-N-(1H-INDOL-4-YL)-1-BENZOTHIOPHENE-2-CARBOXAMIDE==
+<StructureSection load='6pgr' size='340' side='right'caption='[[6pgr]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+== Structural highlights ==
+<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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</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='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>
+</table>
+== Function ==
+[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;">
+== 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.
-Authors: Klein, M.G., Ambrus-Aikelin, G.
+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<ref>PMID:32142284</ref>
-Description: Cocomplex structure of Deoxyhypusine synthase with inhibitor 6-BROMO-N-(1H-INDOL-4-YL)-1-BENZOTHIOPHENE-2-CARBOXAMIDE
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Ambrus-Aikelin, G]]
+<div class="pdbe-citations 6pgr" style="background-color:#fffaf0;"></div>
-[[Category: Klein, M.G]]
+==See Also==
+*[[Deoxyhypusine synthase|Deoxyhypusine synthase]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Ambrus-Aikelin G]]
+[[Category: Klein MG]]