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==Co-crystal structure of NAMPT dimer with KPT-9274== | ==Co-crystal structure of NAMPT dimer with KPT-9274== | ||
<StructureSection load='5nsd' size='340' side='right' caption='[[5nsd]], [[Resolution|resolution]] 2.05Å' scene=''> | <StructureSection load='5nsd' size='340' side='right'caption='[[5nsd]], [[Resolution|resolution]] 2.05Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5nsd]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NSD OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5nsd]] 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=5NSD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NSD FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=96Q:(~{E})-3-(6-azanylpyridin-3-yl)-~{N}-[[5-[4-[4,4-bis(fluoranyl)piperidin-1-yl]carbonylphenyl]-7-(4-fluorophenyl)-1-benzofuran-2-yl]methyl]prop-2-enamide'>96Q</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.046Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=96Q:(~{E})-3-(6-azanylpyridin-3-yl)-~{N}-[[5-[4-[4,4-bis(fluoranyl)piperidin-1-yl]carbonylphenyl]-7-(4-fluorophenyl)-1-benzofuran-2-yl]methyl]prop-2-enamide'>96Q</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5nsd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nsd OCA], [https://pdbe.org/5nsd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nsd RCSB], [https://www.ebi.ac.uk/pdbsum/5nsd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nsd ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/NAMPT_HUMAN NAMPT_HUMAN] Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway (By similarity). | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Unraveling the mechanism of action and molecular target of small molecules remains a major challenge in drug discovery. While many cancer drugs target genetic vulnerabilities, loss-of-function screens fail to identify essential genes in drug mechanism of action. Here, we report CRISPRres, a CRISPR-Cas-based genetic screening approach to rapidly derive and identify drug resistance mutations in essential genes. It exploits the local genetic variation created by CRISPR-Cas-induced non-homologous end-joining (NHEJ) repair to generate a wide variety of functional in-frame mutations. Using large sgRNA tiling libraries and known drug-target pairs, we validate it as a target identification approach. We apply CRISPRres to the anticancer agent KPT-9274 and identify nicotinamide phosphoribosyltransferase (NAMPT) as its main target. These results present a powerful and simple genetic approach to create many protein variants that, in combination with positive selection, can be applied to reveal the cellular target of small-molecule inhibitors. | |||
Target identification of small molecules using large-scale CRISPR-Cas mutagenesis scanning of essential genes.,Neggers JE, Kwanten B, Dierckx T, Noguchi H, Voet A, Bral L, Minner K, Massant B, Kint N, Delforge M, Vercruysse T, Baloglu E, Senapedis W, Jacquemyn M, Daelemans D Nat Commun. 2018 Feb 5;9(1):502. doi: 10.1038/s41467-017-02349-8. PMID:29402884<ref>PMID:29402884</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5nsd" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Baloglu | [[Category: Large Structures]] | ||
[[Category: Daelemans | [[Category: Baloglu E]] | ||
[[Category: Dierckx | [[Category: Daelemans D]] | ||
[[Category: Jacquemyn | [[Category: Dierckx T]] | ||
[[Category: Kwanten | [[Category: Jacquemyn M]] | ||
[[Category: Neggers | [[Category: Kwanten B]] | ||
[[Category: Noguchi | [[Category: Neggers JE]] | ||
[[Category: Senapedis | [[Category: Noguchi H]] | ||
[[Category: Vercruysse | [[Category: Senapedis W]] | ||
[[Category: Voet | [[Category: Vercruysse T]] | ||
[[Category: Voet A]] | |||
Latest revision as of 15:05, 22 November 2023
Co-crystal structure of NAMPT dimer with KPT-9274Co-crystal structure of NAMPT dimer with KPT-9274
Structural highlights
FunctionNAMPT_HUMAN Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway (By similarity). Publication Abstract from PubMedUnraveling the mechanism of action and molecular target of small molecules remains a major challenge in drug discovery. While many cancer drugs target genetic vulnerabilities, loss-of-function screens fail to identify essential genes in drug mechanism of action. Here, we report CRISPRres, a CRISPR-Cas-based genetic screening approach to rapidly derive and identify drug resistance mutations in essential genes. It exploits the local genetic variation created by CRISPR-Cas-induced non-homologous end-joining (NHEJ) repair to generate a wide variety of functional in-frame mutations. Using large sgRNA tiling libraries and known drug-target pairs, we validate it as a target identification approach. We apply CRISPRres to the anticancer agent KPT-9274 and identify nicotinamide phosphoribosyltransferase (NAMPT) as its main target. These results present a powerful and simple genetic approach to create many protein variants that, in combination with positive selection, can be applied to reveal the cellular target of small-molecule inhibitors. Target identification of small molecules using large-scale CRISPR-Cas mutagenesis scanning of essential genes.,Neggers JE, Kwanten B, Dierckx T, Noguchi H, Voet A, Bral L, Minner K, Massant B, Kint N, Delforge M, Vercruysse T, Baloglu E, Senapedis W, Jacquemyn M, Daelemans D Nat Commun. 2018 Feb 5;9(1):502. doi: 10.1038/s41467-017-02349-8. PMID:29402884[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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