5I8R

aSMase with zinc

Summary for 5I8R

• Entry DOI: 10.2210/pdb5i8r/pdb
• Related: 5I81 5I85
• Descriptor: Sphingomyelin phosphodiesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: acid sphingomyelinase, olipudase alfa, zinc, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 201859.98

Authors

Zhou, Y.F.,Wei, R.R. (deposition date: 2016-02-19, release date: 2016-09-07, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.646 Å)