The hydrogen bonds between Arg423 and Glu472 and other key residues, Asp443, Ser477, and Pro489, are responsible for the formation and a different positioning of TNP-ATP and ATP within the nucleotide-binding site of Na(+)/K(+)-ATPase

Biochemistry
Zdenek LanskyEvzen Amler

Abstract

Mutation of Arg(423) at the N-domain of Na(+)/K(+)-ATPase resulted in a large decrease of both TNP-ATP and ATP binding. Thus, this residue, localized outside the binding pocket, seems to play a key role in supporting the proper structure and shape of the binding site. In addition, mutation of Glu(472) also caused a large decrease of both TNP-ATP and ATP binding. On the basis of our computer model, we hypothesized that a hydrogen bond between Arg(423) and Glu(472) supports the connection of two opposite halves of the ATP-binding pocket. To verify this hypothesis, we have also prepared the construct containing both these mutations. Binding of neither TNP-ATP nor ATP to this double mutant differed from binding to any of the single mutants. This strongly supported the existence of the hydrogen bond between Arg(423) and Glu(472). Similarly, the conserved residue Pro(489) seems to be substantial for the proper interaction of the third and fourth beta-strands of the N-domain, which both contain residues that take part in ATP binding. Mutation of Asp(443) affected only ATP, but not TNP-ATP, binding, suggesting that these ligands adopt different positions in the nucleotide-binding pocket. On the basis of a recently published crystal str...Continue Reading

References

Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Aug 1, 1996·Journal of Computer-aided Molecular Design·G M MorrisA J Olson
Mar 29, 2001·Nature Structural Biology·A M BilwesM I Simon
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Jan 14, 2003·Annual Review of Physiology·Peter L JorgensenSteven J D Karlish
Sep 23, 2003·Journal of Molecular Biology·Kjell O Håkansson

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Citations

Sep 18, 2004·European Journal of Biochemistry·Rita KrumscheidWilhelm Schoner
Feb 24, 2009·Biochimica Et Biophysica Acta·Lenka GrycovaMartin Kubala
Mar 27, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Jaroslava ŠeflováMartin Kubala
Aug 21, 2007·Archives of Biochemistry and Biophysics·Lenka GrycovaJan Teisinger

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