4AQ0

Structure of the Gh92 Family Glycosyl Hydrolase Ccman5 in complex with deoxymannojirimycin

4AQ0 の概要

• エントリーDOI: 10.2210/pdb4aq0/pdb
• 分子名称: CCMAN5, CALCIUM ION, 2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (5 entities in total)
• 機能のキーワード: hydrolase, mannosidase
• 由来する生物種: CELLULOSIMICROBIUM CELLULANS
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 169111.37

構造登録者

Baranova, E.,Tiels, P.,Callewaert, N.,Remaut, H. (登録日: 2012-04-12, 公開日: 2013-02-06, 最終更新日: 2023-12-20)

主引用文献

Tiels, P.,Baranova, E.,Piens, K.,De Visscher, C.,Pynaert, G.,Nerinckx, W.,Stout, J.,Fudalej, F.,Hulpiau, P.,Tannler, S.,Geysens, S.,Van Hecke, A.,Valevska, A.,Vervecken, W.,Remaut, H.,Callewaert, N.
A Bacterial Glycosidase Enables Mannose-6-Phosphate Modification and Improved Cellular Uptake of Yeast-Produced Recombinant Human Lysosomal Enzymes.
Nat.Biotechnol., 30:1225-, 2012

PubMed Abstract: Lysosomal storage diseases are treated with human lysosomal enzymes produced in mammalian cells. Such enzyme therapeutics contain relatively low levels of mannose-6-phosphate, which is required to target them to the lysosomes of patient cells. Here we describe a method for increasing mannose-6-phosphate modification of lysosomal enzymes produced in yeast. We identified a glycosidase from C. cellulans that 'uncaps' N-glycans modified by yeast-type mannose-Pi-6-mannose to generate mammalian-type N-glycans with a mannose-6-phosphate substitution. Determination of the crystal structure of this glycosidase provided insight into its substrate specificity. We used this uncapping enzyme together with α-mannosidase to produce in yeast a form of the Pompe disease enzyme α-glucosidase rich in mannose-6-phosphate. Compared with the currently used therapeutic version, this form of α-glucosidase was more efficiently taken up by fibroblasts from Pompe disease patients, and it more effectively reduced cardiac muscular glycogen storage in a mouse model of the disease.

PubMed: 23159880
DOI: 10.1038/NBT.2427

実験手法

X-RAY DIFFRACTION (2.09 Å)