3DKJ

Crystal structure of human NAMPT complexed with benzamide and phosphoribosyl pyrophosphate

Summary for 3DKJ

• Entry DOI: 10.2210/pdb3dkj/pdb
• Related: 3DGR 3DHD 3DHF 3DKL
• Descriptor: Nicotinamide phosphoribosyltransferase, 1-O-pyrophosphono-5-O-phosphono-alpha-D-ribofuranose, BENZAMIDE, ... (4 entities in total)
• Functional Keywords: transferase, nmprtase, visfatin, benzamide, phosphoribosyl pyrophosphate, prpp, nicotinamide phosphoribosyltransferase, alternative splicing, cytoplasm, glycosyltransferase, phosphoprotein, polymorphism, pyridine nucleotide biosynthesis
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 110632.63

Authors

Ho, M.,Burgos, E.S.,Almo, S.C.,Schramm, V.L. (deposition date: 2008-06-25, release date: 2009-08-18, Last modification date: 2023-08-30)

Primary citation

Burgos, E.S.,Ho, M.C.,Almo, S.C.,Schramm, V.L.
A phosphoenzyme mimic, overlapping catalytic sites and reaction coordinate motion for human NAMPT.
Proc.Natl.Acad.Sci.USA, 106:13748-13753, 2009

PubMed Abstract: Nicotinamide phosphoribosyltransferase (NAMPT) is highly evolved to capture nicotinamide (NAM) and replenish the nicotinamide adenine dinucleotide (NAD(+)) pool during ADP-ribosylation and transferase reactions. ATP-phosphorylation of an active-site histidine causes catalytic activation, increasing NAM affinity by 160,000. Crystal structures of NAMPT with catalytic site ligands identify the phosphorylation site, establish its role in catalysis, demonstrate unique overlapping ATP and phosphoribosyltransferase sites, and establish reaction coordinate motion. NAMPT structures with beryllium fluoride indicate a covalent H247-BeF(3)(-) as the phosphohistidine mimic. Activation of NAMPT by H247-phosphorylation causes stabilization of the enzyme-phosphoribosylpyrophosphate complex, permitting efficient capture of NAM. Reactant and product structures establish reaction coordinate motion for NAMPT to be migration of the ribosyl anomeric carbon from the pyrophosphate leaving group to the nicotinamide-N1 while the 5-phosphoryl group, the pyrophosphate moiety, and the nicotinamide ring remain fixed in the catalytic site.

PubMed: 19666527
DOI: 10.1073/pnas.0903898106

Experimental method

X-RAY DIFFRACTION (2 Å)