5I81
aSMase with zinc
Summary for 5I81
Entry DOI | 10.2210/pdb5i81/pdb |
Related | 5I85 5I8R |
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, ... (9 entities in total) |
Functional Keywords | acid sphingomyelinase, hydrolase |
Biological source | Homo sapiens (Human) |
Total number of polymer chains | 1 |
Total formula weight | 69162.43 |
Authors | Zhou, Y.F.,Wei, R.R. (deposition date: 2016-02-18, release date: 2016-09-07, Last modification date: 2024-11-13) |
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 Cited by 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: 27725636DOI: 10.1038/ncomms13082 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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