4irp Citations

Crystal Structures of β-1,4-Galactosyltransferase 7 Enzyme Reveal Conformational Changes and Substrate Binding.

J. Biol. Chem. 288 31963-70 (2013)
Related entries: 4irq, 4lw3, 4lw6, 4m4k

Cited: 16 times
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Abstract

The β-1,4-galactosyltransferase 7 (β4GalT7) enzyme is involved in proteoglycan synthesis. In the presence of a manganese ion, it transfers galactose from UDP-galactose to xylose on a proteoglycan acceptor substrate. We present here the crystal structures of human β4GalT7 in open and closed conformations. A comparison of these crystal structures shows that, upon manganese and UDP or UDP-Gal binding, the enzyme undergoes conformational changes involving a small and a long loop. We also present the crystal structures of Drosophila wild-type β4GalT7 and D211N β4GalT7 mutant enzymes in the closed conformation in the presence of the acceptor substrate xylobiose and the donor substrate UDP-Gal, respectively. To understand the catalytic mechanism, we have crystallized the ternary complex of D211N β4GalT7 mutant enzyme in the presence of manganese with the donor and the acceptor substrates together in the same crystal structure. The galactose moiety of the bound UDP-Gal molecule forms seven hydrogen bonds with the protein molecule. The nonreducing end of the xylose moiety of xylobiose binds to the hydrophobic acceptor sugar binding pocket created by the conformational changes, whereas its extended xylose moiety forms hydrophobic interactions with a Tyr residue. In the ternary complex crystal structure, the nucleophile O4 oxygen atom of the xylose molecule is found in close proximity to the C1 and O5 atoms of the galactose moiety. This is the first time that a Michaelis complex of a glycosyltransferase has been described, and it clearly suggests an SN2 type catalytic mechanism for the β4GalT7 enzyme.

Articles - 4irp mentioned but not cited (1)

  1. Crystal structures of β-1,4-galactosyltransferase 7 enzyme reveal conformational changes and substrate binding. Tsutsui Y, Ramakrishnan B, Qasba PK. J. Biol. Chem. 288 31963-31970 (2013)


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  2. Crystal structures of eukaryote glycosyltransferases reveal biologically relevant enzyme homooligomers. Harrus D, Kellokumpu S, Glumoff T. Cell. Mol. Life Sci. 75 833-848 (2018)
  3. Current insights into the molecular genetic basis of dwarfism in livestock. Boegheim IJM, Leegwater PAJ, van Lith HA, Back W. Vet. J. 224 64-75 (2017)
  4. Epigenetic Regulation of the Biosynthesis & Enzymatic Modification of Heparan Sulfate Proteoglycans: Implications for Tumorigenesis and Cancer Biomarkers. Hull EE, Montgomery MR, Leyva KJ. Int J Mol Sci 18 (2017)
  5. The conformational plasticity of glycosyltransferases. Albesa-Jové D, Guerin ME. Curr. Opin. Struct. Biol. 40 23-32 (2016)
  6. A molecular description of cellulose biosynthesis. McNamara JT, Morgan JL, Zimmer J. Annu. Rev. Biochem. 84 895-921 (2015)
  7. Glycosyltransferases: mechanisms and applications in natural product development. Liang DM, Liu JH, Wu H, Wang BB, Zhu HJ, Qiao JJ. Chem Soc Rev 44 8350-8374 (2015)
  8. Advances in understanding glycosyltransferases from a structural perspective. Gloster TM. Curr. Opin. Struct. Biol. 28 131-141 (2014)
  9. Crossroads between Bacterial and Mammalian Glycosyltransferases. Brockhausen I. Front Immunol 5 492 (2014)

Articles citing this publication (6)

  1. Exploration of the active site of β4GalT7: modifications of the aglycon of aromatic xylosides. Siegbahn A, Thorsheim K, Ståhle J, Manner S, Hamark C, Persson A, Tykesson E, Mani K, Westergren-Thorsson G, Widmalm G, Ellervik U. Org. Biomol. Chem. 13 3351-3362 (2015)
  2. Structure and Mechanism of Staphylococcus aureus TarS, the Wall Teichoic Acid β-glycosyltransferase Involved in Methicillin Resistance. Sobhanifar S, Worrall LJ, King DT, Wasney GA, Baumann L, Gale RT, Nosella M, Brown ED, Withers SG, Strynadka NC. PLoS Pathog. 12 e1006067 (2016)
  3. Probing the acceptor active site organization of the human recombinant β1,4-galactosyltransferase 7 and design of xyloside-based inhibitors. Saliba M, Ramalanjaona N, Gulberti S, Bertin-Jung I, Thomas A, Dahbi S, Lopin-Bon C, Jacquinet JC, Breton C, Ouzzine M, Fournel-Gigleux S. J. Biol. Chem. 290 7658-7670 (2015)
  4. Binding of NAD+ and L-threonine induces stepwise structural and flexibility changes in Cupriavidus necator L-threonine dehydrogenase. Nakano S, Okazaki S, Tokiwa H, Asano Y. J. Biol. Chem. 289 10445-10454 (2014)
  5. 'Click'-xylosides as initiators of the biosynthesis of glycosaminoglycans: Comparison of mono-xylosides with xylobiosides. Chatron-Colliet A, Brusa C, Bertin-Jung I, Gulberti S, Ramalanjaona N, Fournel-Gigleux S, Brézillon S, Muzard M, Plantier-Royon R, Rémond C, Wegrowski Y. Chem Biol Drug Des 89 319-326 (2017)
  6. Synthesis of a library of variously modified 4-methylumbelliferyl xylosides and a structure-activity study of human β4GalT7. Dahbi S, Jacquinet JC, Bertin-Jung I, Robert A, Ramalanjaona N, Gulberti S, Fournel-Gigleux S, Lopin-Bon C. Org. Biomol. Chem. 15 9653-9669 (2017)