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==Structural Analysis of a Phosphoribosylated Inhibitor in Complex with Human Nicotinamide Phosphoribosyltransferase==
==Structural Analysis of a Phosphoribosylated Inhibitor in Complex with Human Nicotinamide Phosphoribosyltransferase==
<StructureSection load='4l4m' size='340' side='right' caption='[[4l4m]], [[Resolution|resolution]] 2.44&Aring;' scene=''>
<StructureSection load='4l4m' size='340' side='right'caption='[[4l4m]], [[Resolution|resolution]] 2.44&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4l4m]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4L4M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4L4M FirstGlance]. <br>
<table><tr><td colspan='2'>[[4l4m]] 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=4L4M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L4M FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1XD:N-{4-[(3,5-DIFLUOROPHENYL)SULFONYL]BENZYL}IMIDAZO[1,2-A]PYRIDINE-7-CARBOXAMIDE'>1XD</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]] 2.445&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4l4l|4l4l]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1XD:N-{4-[(3,5-DIFLUOROPHENYL)SULFONYL]BENZYL}IMIDAZO[1,2-A]PYRIDINE-7-CARBOXAMIDE'>1XD</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4l4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l4m OCA], [https://pdbe.org/4l4m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l4m RCSB], [https://www.ebi.ac.uk/pdbsum/4l4m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l4m 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=4l4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l4m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4l4m RCSB], [http://www.ebi.ac.uk/pdbsum/4l4m PDBsum]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[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).
Prolonged inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a strategy for targeting cancer metabolism. Many NAMPT inhibitors undergo NAMPT-catalyzed phosphoribosylation (pRib), a property often correlated with their cellular potency. To understand this phenomenon and facilitate drug design, we analyzed a potent cellularly active NAMPT inhibitor (GNE-617). A crystal structure of pRib-GNE-617 in complex with NAMPT protein revealed a relaxed binding mode. Consistently, the adduct formation resulted in tight binding and strong product inhibition. In contrast, a biochemically equipotent isomer of GNE-617 (GNE-643) also formed pRib adducts but displayed significantly weaker cytotoxicity. Structural analysis revealed an altered ligand conformation of GNE-643, thus suggesting weak association of the adducts with NAMPT. Our data support a model for cellularly active NAMPT inhibitors that undergo NAMPT-catalyzed phosphoribosylation to produce pRib adducts that retain efficient binding to the enzyme.
 
Structural and biochemical analyses of the catalysis and potency impact of inhibitor phosphoribosylation by human nicotinamide phosphoribosyltransferase.,Oh A, Ho YC, Zak M, Liu Y, Chen X, Yuen PW, Zheng X, Liu Y, Dragovich PS, Wang W Chembiochem. 2014 May 26;15(8):1121-30. doi: 10.1002/cbic.201402023. Epub 2014, May 5. PMID:24797455<ref>PMID:24797455</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Nicotinamide phosphoribosyltransferase]]
[[Category: Homo sapiens]]
[[Category: Dragovich, S P.]]
[[Category: Large Structures]]
[[Category: Ho, Y.]]
[[Category: Dragovich SP]]
[[Category: Liu, Y.]]
[[Category: Ho Y]]
[[Category: Oh, A.]]
[[Category: Liu Y]]
[[Category: Wang, W.]]
[[Category: Oh A]]
[[Category: Yuen, P.]]
[[Category: Wang W]]
[[Category: Zak, M.]]
[[Category: Yuen P]]
[[Category: Zheng, X.]]
[[Category: Zak M]]
[[Category: Active site]]
[[Category: Zheng X]]
[[Category: Inhibitor]]
[[Category: Transferase]]
[[Category: Transferase-transferase inhibitor complex]]

Latest revision as of 15:17, 1 March 2024

Structural Analysis of a Phosphoribosylated Inhibitor in Complex with Human Nicotinamide PhosphoribosyltransferaseStructural Analysis of a Phosphoribosylated Inhibitor in Complex with Human Nicotinamide Phosphoribosyltransferase

Structural highlights

4l4m is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.445Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).

See Also

4l4m, resolution 2.44Å

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