5FIC

Open form of murine Acid Sphingomyelinase in presence of lipid

5FIC の概要

• エントリーDOI: 10.2210/pdb5fic/pdb
• 関連するPDBエントリー: 5FI9 5FIB
• 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, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: smpd1, asm, asmase, saposin, hydrolase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 247366.20

構造登録者

Gorelik, A.,Illes, K.,Heinz, L.X.,Superti-Furga, G.,Nagar, B. (登録日: 2015-12-22, 公開日: 2016-07-06, 最終更新日: 2024-10-30)

主引用文献

Gorelik, A.,Illes, K.,Heinz, L.X.,Superti-Furga, G.,Nagar, B.
Crystal structure of mammalian acid sphingomyelinase.
Nat Commun, 7:12196-12196, 2016

PubMed Abstract: Acid sphingomyelinase (ASMase, ASM, SMPD1) converts sphingomyelin into ceramide, modulating membrane properties and signal transduction. Inactivating mutations in ASMase cause Niemann-Pick disease, and its inhibition is also beneficial in models of depression and cancer. To gain a better understanding of this critical therapeutic target, we determined crystal structures of mammalian ASMase in various conformations. The catalytic domain adopts a calcineurin-like fold with two zinc ions and a hydrophobic track leading to the active site. Strikingly, the membrane interacting saposin domain assumes either a closed globular conformation independent from the catalytic domain, or an open conformation, which establishes an interface with the catalytic domain essential for activity. Structural mapping of Niemann-Pick mutations reveals that most of them likely destabilize the protein's fold. This study sheds light on the molecular mechanism of ASMase function, and provides a platform for the rational development of ASMase inhibitors and therapeutic use of recombinant ASMase.

PubMed: 27435900
DOI: 10.1038/ncomms12196

実験手法

X-RAY DIFFRACTION (2.8 Å)