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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4o15]] 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=4O15 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4O15 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4o15]] 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=4O15 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4O15 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2P1:N-(4-{[3-(TRIFLUOROMETHYL)PHENYL]SULFONYL}BENZYL)-2H-PYRAZOLO[3,4-B]PYRIDINE-5-CARBOXAMIDE'>2P1</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2P1:N-(4-{[3-(TRIFLUOROMETHYL)PHENYL]SULFONYL}BENZYL)-2H-PYRAZOLO[3,4-B]PYRIDINE-5-CARBOXAMIDE'>2P1</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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'>[https://proteopedia.org/fgij/fg.htm?mol=4o15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o15 OCA], [https://pdbe.org/4o15 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4o15 RCSB], [https://www.ebi.ac.uk/pdbsum/4o15 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4o15 ProSAT]</span></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=4o15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o15 OCA], [https://pdbe.org/4o15 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4o15 RCSB], [https://www.ebi.ac.uk/pdbsum/4o15 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4o15 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).
[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 ==
Inhibiting NAD biosynthesis by blocking the function of nicotinamide phosphoribosyl transferase (NAMPT) is an attractive therapeutic strategy for targeting tumor metabolism. However, the development of drug resistance commonly limits the efficacy of cancer therapeutics. This study identifies mutations in NAMPT that confer resistance to a novel NAMPT inhibitor, GNE-618, in cell culture and in vivo, thus demonstrating that the cytotoxicity of GNE-618 is on target. We determine the crystal structures of six NAMPT mutants in the apo form and in complex with various inhibitors and use cellular, biochemical and structural data to elucidate two resistance mechanisms. One is the surprising finding of allosteric modulation by mutation of residue Ser165, resulting in unwinding of an alpha-helix that binds the NAMPT substrate 5-phosphoribosyl-1-pyrophosphate (PRPP). The other mechanism is orthosteric blocking of inhibitor binding by mutations of Gly217. Furthermore, by evaluating a panel of diverse small molecule inhibitors, we unravel inhibitor structure activity relationships on the mutant enzymes. These results provide valuable insights into the design of next generation NAMPT inhibitors that offer improved therapeutic potential by evading certain mechanisms of resistance.
Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors.,Wang W, Elkins K, Oh A, Ho YC, Wu J, Li H, Xiao Y, Kwong M, Coons M, Brillantes B, Cheng E, Crocker L, Dragovich PS, Sampath D, Zheng X, Bair KW, O'Brien T, Belmont LD PLoS One. 2014 Oct 6;9(10):e109366. doi: 10.1371/journal.pone.0109366., eCollection 2014. PMID:25285661<ref>PMID:25285661</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4o15" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
== References ==
<references/>
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</StructureSection>
</StructureSection>

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