4o18 - Revision history

OCA at 12:37, 1 March 2024

2024-03-01T12:37:06Z

←Older revision		Revision as of 12:37, 1 March 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4o18]] 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=4O18 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4O18 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4o18]] 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=4O18 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4O18 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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]] 1.92Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [https://pdbe.org/4o18 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [https://www.ebi.ac.uk/pdbsum/4o18 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4o18 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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [https://pdbe.org/4o18 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [https://www.ebi.ac.uk/pdbsum/4o18 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4o18 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®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4o18" style="background-color:#fffaf0;"></div>

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

OCA at 08:51, 18 January 2023

2023-01-18T08:51:18Z

←Older revision		Revision as of 08:51, 18 January 2023
Line 3:		Line 3:
	<StructureSection load='4o18' size='340' side='right'caption='[[4o18]], [[Resolution\|resolution]] 1.92Å' scene=''>		<StructureSection load='4o18' size='340' side='right'caption='[[4o18]], [[Resolution\|resolution]] 1.92Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4o18]] 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=4O18 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4O18 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4o18]] 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=4O18 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4O18 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4o13\|4o13]], [[4o14\|4o14]], [[4o15\|4o15]], [[4o16\|4o16]], [[4o17\|4o17]], [[4o19\|4o19]], [[4o1a\|4o1a]], [[4o1b\|4o1b]], [[4o1c\|4o1c]], [[4o1d\|4o1d]], [[4o28\|4o28]]</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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [https://pdbe.org/4o18 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [https://www.ebi.ac.uk/pdbsum/4o18 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4o18 ProSAT]</span></td></tr>
-	<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>	+
-	<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>	+
-	<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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [~~http~~://pdbe.org/4o18 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4o18 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4o18 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[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).	+	[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 23:		Line 20:

	==See Also==		==See Also==
-	*[[Phosphoribosyltransferase\|Phosphoribosyltransferase]]	+	*[[Phosphoribosyltransferase 3D structures\|Phosphoribosyltransferase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Nicotinamide phosphoribosyltransferase]]~~	+	[[Category: Brillantes B]]
-	[[Category: Brillantes, B]]	+	[[Category: Coons M]]
-	[[Category: Coons, M]]	+	[[Category: Oh A]]
-	[[Category: Oh, A]]	+	[[Category: Wang W]]
-	[[Category: Wang, W]]	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 08:48, 10 April 2019

2019-04-10T08:48:32Z

←Older revision		Revision as of 08:48, 10 April 2019
Line 1:		Line 1:

	==Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors==		==Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors==
-	<StructureSection load='4o18' size='340' side='right' caption='[[4o18]], [[Resolution\|resolution]] 1.92Å' scene=''>	+	<StructureSection load='4o18' size='340' side='right'caption='[[4o18]], [[Resolution\|resolution]] 1.92Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4o18]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4O18 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4O18 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4o18]] 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=4O18 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4O18 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4o13\|4o13]], [[4o14\|4o14]], [[4o15\|4o15]], [[4o16\|4o16]], [[4o17\|4o17]], [[4o19\|4o19]], [[4o1a\|4o1a]], [[4o1b\|4o1b]], [[4o1c\|4o1c]], [[4o1d\|4o1d]], [[4o28\|4o28]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4o13\|4o13]], [[4o14\|4o14]], [[4o15\|4o15]], [[4o16\|4o16]], [[4o17\|4o17]], [[4o19\|4o19]], [[4o1a\|4o1a]], [[4o1b\|4o1b]], [[4o1c\|4o1c]], [[4o1d\|4o1d]], [[4o28\|4o28]]</td></tr>
		+	<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>
	<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>		<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>
	<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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [http://pdbe.org/4o18 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [http://www.ebi.ac.uk/pdbsum/4o18 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4o18 ProSAT]</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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [http://pdbe.org/4o18 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [http://www.ebi.ac.uk/pdbsum/4o18 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4o18 ProSAT]</span></td></tr>
Line 27:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Nicotinamide phosphoribosyltransferase]]		[[Category: Nicotinamide phosphoribosyltransferase]]
	[[Category: Brillantes, B]]		[[Category: Brillantes, B]]

OCA at 00:44, 5 August 2016

2016-08-05T00:44:12Z

←Older revision		Revision as of 00:44, 5 August 2016
Line 1:		Line 1:
		+
	==Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors==		==Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors==
	<StructureSection load='4o18' size='340' side='right' caption='[[4o18]], [[Resolution\|resolution]] 1.92Å' scene=''>		<StructureSection load='4o18' size='340' side='right' caption='[[4o18]], [[Resolution\|resolution]] 1.92Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4o13\|4o13]], [[4o14\|4o14]], [[4o15\|4o15]], [[4o16\|4o16]], [[4o17\|4o17]], [[4o19\|4o19]], [[4o1a\|4o1a]], [[4o1b\|4o1b]], [[4o1c\|4o1c]], [[4o1d\|4o1d]], [[4o28\|4o28]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4o13\|4o13]], [[4o14\|4o14]], [[4o15\|4o15]], [[4o16\|4o16]], [[4o17\|4o17]], [[4o19\|4o19]], [[4o1a\|4o1a]], [[4o1b\|4o1b]], [[4o1c\|4o1c]], [[4o1d\|4o1d]], [[4o28\|4o28]]</td></tr>
	<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>		<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>
-	<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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [http://www.ebi.ac.uk/pdbsum/4o18 PDBsum]</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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [http://pdbe.org/4o18 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [http://www.ebi.ac.uk/pdbsum/4o18 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4o18 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4o18" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Phosphoribosyltransferase\|Phosphoribosyltransferase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 21:18, 24 December 2014

2014-12-24T21:18:07Z

←Older revision		Revision as of 21:18, 24 December 2014
Line 8:		Line 8:
	<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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [http://www.ebi.ac.uk/pdbsum/4o18 PDBsum]</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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [http://www.ebi.ac.uk/pdbsum/4o18 PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[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).
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 21:		Line 23:
	</StructureSection>		</StructureSection>
	[[Category: Nicotinamide phosphoribosyltransferase]]		[[Category: Nicotinamide phosphoribosyltransferase]]
-	[[Category: Brillantes, B.]]	+	[[Category: Brillantes, B]]
-	[[Category: Coons, M.]]	+	[[Category: Coons, M]]
-	[[Category: Oh, A.]]	+	[[Category: Oh, A]]
-	[[Category: Wang, W.]]	+	[[Category: Wang, W]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 11:39, 22 October 2014

2014-10-22T11:39:59Z

←Older revision		Revision as of 11:39, 22 October 2014
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors==
		+	<StructureSection load='4o18' size='340' side='right' caption='[[4o18]], [[Resolution\|resolution]] 1.92Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4o18]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4O18 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4O18 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4o13\|4o13]], [[4o14\|4o14]], [[4o15\|4o15]], [[4o16\|4o16]], [[4o17\|4o17]], [[4o19\|4o19]], [[4o1a\|4o1a]], [[4o1b\|4o1b]], [[4o1c\|4o1c]], [[4o1d\|4o1d]], [[4o28\|4o28]]</td></tr>
		+	<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>
		+	<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=4o18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o18 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4o18 RCSB], [http://www.ebi.ac.uk/pdbsum/4o18 PDBsum]</span></td></tr>
		+	</table>
		+	<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.

-	~~The entry 4o18 is ON HOLD until Paper Publication~~	+	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>

-	~~Authors: Oh~~, A., Coons, M., ~~Brillantes, B~~., Wang, W.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors~~	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Nicotinamide phosphoribosyltransferase]]
		+	[[Category: Brillantes, B.]]
		+	[[Category: Coons, M.]]
		+	[[Category: Oh, A.]]
		+	[[Category: Wang, W.]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 10:22, 5 February 2014

2014-02-05T10:22:46Z

←Older revision		Revision as of 10:22, 5 February 2014
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-	The entry 4o18 is ON HOLD	+	The entry 4o18 is ON HOLD until Paper Publication

	Authors: Oh, A., Coons, M., Brillantes, B., Wang, W.		Authors: Oh, A., Coons, M., Brillantes, B., Wang, W.

	Description: Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors		Description: Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors

OCA at 09:21, 8 January 2014

2014-01-08T09:21:36Z

←Older revision		Revision as of 09:21, 8 January 2014
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	The entry 4o18 is ON HOLD		The entry 4o18 is ON HOLD

-	Authors: Oh, A., Coons, M., Brillantes, B., Wang, W	+	Authors: Oh, A., Coons, M., Brillantes, B., Wang, W.

	Description: Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors		Description: Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors

OCA: Protected "4o18" [edit=sysop:move=sysop]

2013-12-25T09:29:59Z

Protected "4o18" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:29, 25 December 2013

OCA: New page: '''Unreleased structure''' The entry 4o18 is ON HOLD Authors: Oh, A., Coons, M., Brillantes, B., Wang, W Description: Structural Basis for Resistance to Diverse Classes of NAMPT Inhibi...

2013-12-25T09:29:58Z

New page: '''Unreleased structure''' The entry 4o18 is ON HOLD Authors: Oh, A., Coons, M., Brillantes, B., Wang, W Description: Structural Basis for Resistance to Diverse Classes of NAMPT Inhibi...

New page

'''Unreleased structure'''

The entry 4o18 is ON HOLD

Authors: Oh, A., Coons, M., Brillantes, B., Wang, W

Description: Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors