5HQN

Catalytic domain of murine Acid Sphingomyelinase (ASMase, ASM, SMPD1)

Summary for 5HQN

• Entry DOI: 10.2210/pdb5hqn/pdb
• Related: 5FI9 5FIB 5FIC
• Descriptor: Sphingomyelin phosphodiesterase, 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, ... (7 entities in total)
• Functional Keywords: smpd1, asm, asmase, sphingomyelinase, hydrolase-hydrolase inhibitor complex, hydrolase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 110938.84

Authors

Gorelik, A.,Illes, K.,Heinz, L.X.,Superti-Furga, G.,Nagar, B. (deposition date: 2016-01-21, release date: 2016-07-06, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)