Elucidation of the ATP7B N-domain Mg2+-ATP coordination site and its allosteric regulation

PLoS One. 2011;6(10):e26245. doi: 10.1371/journal.pone.0026245. Epub 2011 Oct 27.

Abstract

The diagnostic of orphan genetic disease is often a puzzling task as less attention is paid to the elucidation of the pathophysiology of these rare disorders at the molecular level. We present here a multidisciplinary approach using molecular modeling tools and surface plasmonic resonance to study the function of the ATP7B protein, which is impaired in the Wilson disease. Experimentally validated in silico models allow the elucidation in the Nucleotide binding domain (N-domain) of the Mg(2+)-ATP coordination site and answer to the controversial role of the Mg(2+) ion in the nucleotide binding process. The analysis of protein motions revealed a substantial effect on a long flexible loop branched to the N-domain protein core. We demonstrated the capacity of the loop to disrupt the interaction between Mg(2+)-ATP complex and the N-domain and propose a role for this loop in the allosteric regulation of the nucleotide binding process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / metabolism*
  • Allosteric Regulation
  • Binding Sites
  • Cation Transport Proteins / chemistry*
  • Cation Transport Proteins / metabolism
  • Computer Simulation
  • Copper-Transporting ATPases
  • Humans
  • Protein Binding
  • Protein Structure, Tertiary

Substances

  • Cation Transport Proteins
  • Adenosine Triphosphatases
  • ATP7B protein, human
  • Copper-Transporting ATPases

Associated data

  • OMIM/OMIM277900