5NDF

Small-molecule inhibition of ppGalNAc-Ts selectively reduces mucin-type O-glycosylation

5NDF の概要

• エントリーDOI: 10.2210/pdb5ndf/pdb
• 分子名称: Polypeptide N-acetylgalactosaminyltransferase 2, MANGANESE (II) ION, URIDINE-5'-DIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: galnac-t2 inhibition flavonoids mucin-type o-glycosylation alzheimer disease, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Golgi apparatus, Golgi stack membrane ; Single-pass type II membrane protein : Q10471
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 393182.20

構造登録者

Hurtado-Guerrero, R.,De las Rivas, M. (登録日: 2017-03-08, 公開日: 2017-11-01, 最終更新日: 2024-01-17)

主引用文献

Liu, F.,Xu, K.,Xu, Z.,de Las Rivas, M.,Wang, C.,Li, X.,Lu, J.,Zhou, Y.,Delso, I.,Merino, P.,Hurtado-Guerrero, R.,Zhang, Y.,Wu, F.
The small molecule luteolin inhibits N-acetyl-alpha-galactosaminyltransferases and reduces mucin-type O-glycosylation of amyloid precursor protein.
J. Biol. Chem., 292:21304-21319, 2017

PubMed Abstract: Mucin-type -glycosylation is the most abundant type of -glycosylation. It is initiated by the members of the polypeptide -acetyl-α-galactosaminyltransferase (ppGalNAc-T) family and closely associated with both physiological and pathological conditions, such as coronary artery disease or Alzheimer's disease. The lack of direct and selective inhibitors of ppGalNAc-Ts has largely impeded research progress in understanding the molecular events in mucin-type -glycosylation. Here, we report that a small molecule, the plant flavonoid luteolin, selectively inhibits ppGalNAc-Ts and in cells. We found that luteolin inhibits ppGalNAc-T2 in a peptide/protein-competitive manner but not promiscuously ( via aggregation-based activity). X-ray structural analysis revealed that luteolin binds to the PP motif-binding site found in most protein substrates, which was further validated by comparing the interactions of luteolin with wild-type enzyme and with mutants using H NMR-based binding experiments. Functional studies disclosed that luteolin at least partially reduced production of β-amyloid protein by selectively inhibiting the activity of ppGalNAc-T isoforms. In conclusion, our study provides key structural and functional details on luteolin inhibiting ppGalNAc-T activity, opening up the way for further optimization of more potent and specific ppGalNAc-T inhibitors. Moreover, our findings may inform future investigations into site-specific -GalNAc glycosylation and into the molecular mechanism of luteolin-mediated ppGalNAc-T inhibition.

PubMed: 29061849
DOI: 10.1074/jbc.M117.814202

実験手法

X-RAY DIFFRACTION (2.3 Å)