4n9c

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==Fragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)==
==Fragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)==
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<StructureSection load='4n9c' size='340' side='right' caption='[[4n9c]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
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<StructureSection load='4n9c' size='340' side='right'caption='[[4n9c]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4n9c]] 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=4N9C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4N9C FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4n9c]] 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=4N9C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N9C FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2ZM:5-NITRO-1H-BENZIMIDAZOLE'>2ZM</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.751&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4n9b|4n9b]], [[4n9d|4n9d]], [[4n9e|4n9e]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2ZM:5-NITRO-1H-BENZIMIDAZOLE'>2ZM</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NAMPT, PBEF, PBEF1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4n9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n9c OCA], [https://pdbe.org/4n9c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n9c RCSB], [https://www.ebi.ac.uk/pdbsum/4n9c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n9c ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nicotinamide_phosphoribosyltransferase Nicotinamide phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.12 2.4.2.12] </span></td></tr>
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<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=4n9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n9c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4n9c RCSB], [http://www.ebi.ac.uk/pdbsum/4n9c PDBsum]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://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).
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[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).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described.
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Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).,Dragovich PS, Zhao G, Baumeister T, Bravo B, Giannetti AM, Ho YC, Hua R, Li G, Liang X, Ma X, O'Brien T, Oh A, Skelton NJ, Wang C, Wang W, Wang Y, Xiao Y, Yuen PW, Zak M, Zhao Q, Zheng X Bioorg Med Chem Lett. 2014 Feb 1;24(3):954-62. doi: 10.1016/j.bmcl.2013.12.062., Epub 2013 Dec 21. PMID:24433859<ref>PMID:24433859</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Phosphoribosyltransferase|Phosphoribosyltransferase]]
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*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Nicotinamide phosphoribosyltransferase]]
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[[Category: Large Structures]]
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[[Category: Baumeister, T]]
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[[Category: Baumeister T]]
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[[Category: Bravo, B]]
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[[Category: Bravo B]]
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[[Category: Brien, T O]]
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[[Category: Dragovich PS]]
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[[Category: Dragovich, P S]]
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[[Category: Giannetti AM]]
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[[Category: Giannetti, A M]]
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[[Category: Ho Y]]
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[[Category: Ho, Y]]
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[[Category: Hua R]]
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[[Category: Hua, R]]
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[[Category: Li G]]
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[[Category: Li, G]]
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[[Category: Liang X]]
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[[Category: Liang, X]]
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[[Category: O'Brien T]]
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[[Category: Oh, A]]
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[[Category: Oh A]]
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[[Category: Skelton, N J]]
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[[Category: Skelton NJ]]
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[[Category: Wang, C]]
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[[Category: Wang C]]
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[[Category: Wang, W]]
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[[Category: Wang W]]
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[[Category: Wang, Y]]
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[[Category: Wang Y]]
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[[Category: Xiao, Y]]
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[[Category: Xiao Y]]
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[[Category: Yuen, P]]
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[[Category: Yuen P]]
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[[Category: Zak, M]]
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[[Category: Zak M]]
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[[Category: Zhao, G]]
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[[Category: Zhao G]]
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[[Category: Zhao, Q]]
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[[Category: Zhao Q]]
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[[Category: Zheng, X]]
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[[Category: Zheng X]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Fragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)

PDB ID 4n9c

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