5i8r | pdb_00005i8r

aSMase with zinc

spinqualitylabelsall models 5i8r, resolution 3.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5i8r is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.646Å Ligands: BMA, MAN, NAG, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ASM_HUMAN Niemann-Pick disease type A;Niemann-Pick disease type B. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Function ASM_HUMAN Converts sphingomyelin to ceramide (PubMed:1840600, PubMed:18815062). Also has phospholipase C activities toward 1,2-diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol. Isoform 2 lacks residues that bind the cofactor Zn(2+) and has no enzyme activity. Isoform 3 lacks residues that bind the cofactor Zn(2+) and has no enzyme activity. Publication Abstract from PubMed 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. Human acid sphingomyelinase structures provide insight to molecular basis of Niemann-Pick disease.,Zhou YF, Metcalf MC, Garman SC, Edmunds T, Qiu H, Wei RR Nat Commun. 2016 Oct 11;7:13082. doi: 10.1038/ncomms13082. PMID:27725636 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Sphingomyelinase

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