5I85

aSMase with zinc and phosphocholine

5I85 の概要

• エントリーDOI: 10.2210/pdb5i85/pdb
• 関連するPDBエントリー: 5I81 5I8R
• 分子名称: Sphingomyelin phosphodiesterase, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-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, ... (9 entities in total)
• 機能のキーワード: acid sphingomyelinase, phosphocholine, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 69071.32

構造登録者

Zhou, Y.F.,Wei, R.R. (登録日: 2016-02-18, 公開日: 2016-09-07, 最終更新日: 2024-11-13)

主引用文献

Zhou, Y.F.,Metcalf, M.C.,Garman, S.C.,Edmunds, T.,Qiu, H.,Wei, R.R.
Human acid sphingomyelinase structures provide insight to molecular basis of Niemann-Pick disease.
Nat Commun, 7:13082-13082, 2016

PubMed Abstract: Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann-Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients.

PubMed: 27725636
DOI: 10.1038/ncomms13082

実験手法

X-RAY DIFFRACTION (2.5 Å)