8dsd

Human NAMPT in complex with substrate NAM and small molecule activator NP-A1-S

spinqualitylabelsall models 8dsd, resolution 1.43Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8dsd 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. Ligands: CL, GOL, NCA, PO4, TIW 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). Publication Abstract from PubMed In aging and disease, cellular nicotinamide adenine dinucleotide (NAD(+)) is depleted by catabolism to nicotinamide (NAM). NAD(+) supplementation is being pursued to enhance human healthspan and lifespan. Activation of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD(+) biosynthesis, has the potential to increase the salvage of NAM. Novel NAMPT-positive allosteric modulators (N-PAMs) were discovered in addition to the demonstration of NAMPT activation by biogenic phenols. The mechanism of activation was revealed through the synthesis of novel chemical probes, new NAMPT co-crystal structures, and enzyme kinetics. Binding to a rear channel in NAMPT regulates NAM binding and turnover, with biochemical observations being replicated by NAD(+) measurements in human cells. The mechanism of action of N-PAMs identifies, for the first time, the role of the rear channel in the regulation of NAMPT turnover coupled to productive and nonproductive NAM binding. The tight regulation of cellular NAMPT via feedback inhibition by NAM, NAD(+), and adenosine 5'-triphosphate (ATP) is differentially regulated by N-PAMs and other activators, indicating that different classes of pharmacological activators may be engineered to restore or enhance NAD(+) levels in affected tissues. Mechanism of Allosteric Modulation of Nicotinamide Phosphoribosyltransferase to Elevate Cellular NAD().,Ratia KM, Shen Z, Gordon-Blake J, Lee H, Laham MS, Krider IS, Christie N, Ackerman-Berrier M, Penton C, Knowles NG, Musku SR, Fu J, Velma GR, Xiong R, Thatcher GRJ Biochemistry. 2023 Feb 21;62(4):923-933. doi: 10.1021/acs.biochem.2c00655. Epub , 2023 Feb 6. PMID:36746631 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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