8P0L

Crystal structure of human O-GlcNAcase in complex with an S-linked CKII peptide

8P0L の概要

• エントリーDOI: 10.2210/pdb8p0l/pdb
• 分子名称: Protein O-GlcNAcase, CYSTEINE, SERINE, ... (5 entities in total)
• 機能のキーワード: carbohydrate, s-glcnac, gh84, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 206489.27

構造登録者

Males, A.,Davies, G.J.,Calvelo, M.,Alteen, M.G.,Vocadlo, D.J.,Rovira, C. (登録日: 2023-05-10, 公開日: 2023-11-29, 最終更新日: 2024-10-16)

主引用文献

Calvelo, M.,Males, A.,Alteen, M.G.,Willems, L.I.,Vocadlo, D.J.,Davies, G.J.,Rovira, C.
Human O -GlcNAcase Uses a Preactivated Boat-skew Substrate Conformation for Catalysis. Evidence from X-ray Crystallography and QM/MM Metadynamics.
Acs Catalysis, 13:13672-13678, 2023

PubMed Abstract: Human -linked β--acetylglucosaminidase (hOGA) is one of the two enzymes involved in nuclear and cytoplasmic protein O-GlcNAcylation, an essential post-translational modification. The enzyme catalyzes the hydrolysis of the GlcNAc--(Ser/Thr) glycosidic bonds via anchimeric assistance through the 2-acetamido group of the GlcNAc sugar. However, the conformational itinerary of the GlcNAc ring during catalysis remains unclear. Here we report the crystal structure of wild type hOGA in complex with a nonhydrolyzable glycopeptide substrate and elucidate the full enzyme catalytic mechanism using QM/MM metadynamics. We show that the enzyme can bind the substrate in either a chair- or a boat-like conformation, but only the latter is catalytically competent, leading to the reaction products via / → [] → and → [] → / conformational itineraries for the first and second catalytic reaction steps, respectively. Our results reconcile previous experimental observations for human and bacterial OGA and will aid the development of more effective OGA inhibitors for diseases associated with impaired -GlcNAcylation.

PubMed: 37969138
DOI: 10.1021/acscatal.3c02378

実験手法

X-RAY DIFFRACTION (2.5 Å)