7QQF

Crystal structure of unliganded MYORG

7QQF の概要

• エントリーDOI: 10.2210/pdb7qqf/pdb
• 関連するPDBエントリー: 7QQG 7QQH
• 分子名称: Myogenesis-regulating glycosidase, alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: gh31, glycoside hydrolase, myorg, net37, galactosidase, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 297953.30

構造登録者

Meek, R.W.,Davies, G.J. (登録日: 2022-01-07, 公開日: 2022-08-31, 最終更新日: 2024-11-13)

主引用文献

Meek, R.W.,Brockerman, J.,Fordwour, O.B.,Zandberg, W.F.,Davies, G.J.,Vocadlo, D.J.
The primary familial brain calcification-associated protein MYORG is an alpha-galactosidase with restricted substrate specificity.
Plos Biol., 20:e3001764-e3001764, 2022

PubMed Abstract: Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link between mutations in myogenesis-regulating glycosidase (MYORG) and the development of this disease. MYORG is a member of glycoside hydrolase (GH) family 31 (GH31) and, like the other mammalian GH31 enzyme α-glucosidase II, this enzyme is found in the lumen of the endoplasmic reticulum (ER). Though presumed to act as an α-glucosidase due to its localization and sequence relatedness to α-glucosidase II, MYORG has never been shown to exhibit catalytic activity. Here, we show that MYORG is an α-galactosidase and present the high-resolution crystal structure of MYORG in complex with substrate and inhibitor. Using these structures, we map detrimental mutations that are associated with MYORG-associated brain calcification and define how these mutations may drive disease progression through loss of enzymatic activity. Finally, we also detail the thermal stabilisation of MYORG afforded by a clinically approved small molecule ligand, opening the possibility of using pharmacological chaperones to enhance the activity of mutant forms of MYORG.

PubMed: 36129849
DOI: 10.1371/journal.pbio.3001764

実験手法

X-RAY DIFFRACTION (2.43 Å)