4o16

Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors

spinqualitylabelsall models 4o16, resolution 1.78Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4o16 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1XC, EDO, PO4 Related: 4o13, 4o14, 4o15, 4o17, 4o18, 4o19, 4o1a, 4o1b, 4o1c, 4o1d, 4o28 Activity: Nicotinamide phosphoribosyltransferase, with EC number 2.4.2.12 Resources: FirstGlance, OCA, RCSB, PDBsum 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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