2arf: Difference between revisions

[[Image:2arf.gif|left|200px]]

'''Solution structure of the Wilson ATPase N-domain in the presence of ATP'''

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.

2ARF is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ARF OCA].  

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 19:23:02 2008''