6p4v: Difference between revisions

Line 1:

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

~~The entry~~ 6p4v is ~~ON HOLD until Paper~~ Publication

==1.65 Angstrom ternary complex of Deoxyhypusine synthase with cofactor NAD and spermidine mimic inhibitor GC7==

== Structural highlights ==

<table><tr><td colspan='2'>[[6p4v]] is a 2 chain structure. 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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P4V FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v2e|5v2e]], [[5v4j|5v4j]]</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=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>

== 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.

== 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: 1~~.~~65 Angstrom ternary complex~~ of ~~Deoxyhypusine synthase with cofactor NAD and spermidine mimic inhibitor GC7~~

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

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

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Large Structures]]

[[Category: Transferase]]

[[Category: Ambrus-Aikelin, G]]

[[Category: Klein, M.G]]

[[Category: Klein, M G]]

[[Category: Deoxyhypusine]]

[[Category: Gc7]]

[[Category: Hypusine]]

[[Category: Nad cofactor]]

[[Category: Spermidine]]

[[Category: Transferase-inhibitor complex]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6p4v is ON HOLD  until Paper Publication
+==1.65 Angstrom ternary complex of Deoxyhypusine synthase with cofactor NAD and spermidine mimic inhibitor GC7==
+<StructureSection load='6p4v' size='340' side='right'caption='[[6p4v]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6p4v]] is a 2 chain structure. 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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P4V FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v2e|5v2e]], [[5v4j|5v4j]]</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=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>
+== 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.
+<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: 1.65 Angstrom ternary complex of Deoxyhypusine synthase with cofactor NAD and spermidine mimic inhibitor GC7
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6p4v" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Transferase]]
 [[Category: Ambrus-Aikelin, G]]
-[[Category: Klein, M.G]]
+[[Category: Klein, M G]]
+[[Category: Deoxyhypusine]]
+[[Category: Gc7]]
+[[Category: Hypusine]]
+[[Category: Nad cofactor]]
+[[Category: Spermidine]]
+[[Category: Transferase-inhibitor complex]]