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We have solved the structure of <jats:styled-content style=\"fixed-case\">SMPDL<\/jats:styled-content>3a revealing a calcineurin\u2010like fold. A dimetal site, glycosylation pattern and a disulfide bond network are likely to be conserved also in human <jats:styled-content style=\"fixed-case\">aSM<\/jats:styled-content>ase. We show that the binuclear site of <jats:styled-content style=\"fixed-case\">SMPDL<\/jats:styled-content>3a is occupied by two Zn<jats:sup>2+<\/jats:sup> ions and that excess Zn<jats:sup>2+<\/jats:sup> leads to inhibition of enzyme activity through binding to additional sites. As an extension of recent biochemical work we uncovered that <jats:styled-content style=\"fixed-case\">SMPDL<\/jats:styled-content>3a catalyses the hydrolysis of several modified nucleotides that include cytidine 5\u2032\u2010diphosphocholine, cytidine diphosphate ethanolamine and <jats:styled-content style=\"fixed-case\">ADP<\/jats:styled-content>\u2010ribose, but not the <jats:styled-content style=\"fixed-case\">aSM<\/jats:styled-content>ase substrate, sphingomyelin. We subsequently determined the structure of <jats:styled-content style=\"fixed-case\">SMPDL<\/jats:styled-content>3a in complex with the product 5\u2032\u2010cytidine monophosphate (<jats:styled-content style=\"fixed-case\">CMP<\/jats:styled-content>), a structure that is consistent with several distinct coordination modes of the substrate\/product in the active site during the reaction cycle. Based on the structure of <jats:styled-content style=\"fixed-case\">CMP<\/jats:styled-content> complexes, we propose a phosphoryl transfer mechanism for <jats:styled-content style=\"fixed-case\">SMPDL<\/jats:styled-content>3a. Finally, a homology model of human <jats:styled-content style=\"fixed-case\">aSM<\/jats:styled-content>ase was constructed to allow for the mapping of selected Niemann\u2013Pick disease mutations on a three\u2010dimensional framework to guide further characterization of their effects on <jats:styled-content style=\"fixed-case\">aSM<\/jats:styled-content>ase function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Database<\/jats:title><jats:p>Structural data are available in the PDB database under the accession numbers <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=5EBB\">5EBB<\/jats:ext-link> and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=5EBE\">5EBE<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.13655","type":"journal-article","created":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T03:04:39Z","timestamp":1453172679000},"page":"1107-1123","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The structure and catalytic mechanism of human sphingomyelin phosphodiesterase like 3a \u2013 an acid sphingomyelinase homologue with a novel nucleotide hydrolase activity"],"prefix":"10.1111","volume":"283","author":[{"given":"Sing Mei","family":"Lim","sequence":"first","affiliation":[{"name":"Division of Biomedical Structural Biology School of Biological Sciences Nanyang Technological University Singapore"},{"name":"Department of Medical Biochemistry and Biophysics Karolinska Institutet Stockholm 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