2arf
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Solution structure of the Wilson ATPase N-domain in the presence of ATP
OverviewOverview
Wilson disease protein (ATP7B) is a copper-transporting P(1B)-type ATPase, that regulates copper homeostasis and biosynthesis of copper-containing, enzymes in human tissues. Inactivation of ATP7B or related ATP7A leads to, severe neurodegenerative disorders, whereas their overexpression, contributes to cancer cell resistance to chemotherapeutics., Copper-transporting ATPases differ from other P-type ATPases in their, topology and the sequence of their nucleotide-binding domain (N-domain)., To gain insight into the structural basis of ATP7B function, we have, solved the structure of the ATP7B N-domain in the presence of ATP by using, heteronuclear multidimensional NMR spectroscopy. The N-domain consists of, a six-stranded beta-sheet with two adjacent alpha-helical hairpins and, unexpectedly, shows higher similarity to the bacterial K(+)-transporting, ATPase KdpB than to the mammalian Ca(2+)-ATPase or Na(+),K(+)-ATPase. The, common core structure of P-type ATPases is retained in the 3D fold of the, N-domain; however, the nucleotide coordination environment of ATP7B within, this fold is different. The residues H1069, G1099, G1101, I1102, G1149, and N1150 conserved in the P(1B)-ATPase subfamily contribute to ATP, binding. Analysis of the frequent disease mutation H1069Q demonstrates, that this mutation does not significantly affect the structure of the, N-domain but prevents tight binding of ATP. The structure of the N-domain, accounts for the disruptive effects of >30 known Wilson disease mutations., The unique features of the N-domain provide a structural basis for the, development of specific inhibitors and regulators of ATP7B.
DiseaseDisease
Known diseases associated with this structure: Wilson disease OMIM:[606882]
About this StructureAbout this Structure
2ARF is a Single protein structure of sequence from Homo sapiens. Active as Copper-exporting ATPase, with EC number 3.6.3.4 Full crystallographic information is available from OCA.
ReferenceReference
Solution structure of the N-domain of Wilson disease protein: distinct nucleotide-binding environment and effects of disease mutations., Dmitriev O, Tsivkovskii R, Abildgaard F, Morgan CT, Markley JL, Lutsenko S, Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5302-7. Epub 2006 Mar 27. PMID:16567646
Page seeded by OCA on Mon Nov 12 20:53:51 2007