Opening of the ADP-bound active site in the ABC transporter ATPase dimer: evidence for a constant contact, alternating sites model for the catalytic cycle

Proteins. 2009 May 1;75(2):387-96. doi: 10.1002/prot.22250.

Abstract

ABC transporters are ubiquitous, ATP-dependent transmembrane pumps. The mechanism by which ATP hydrolysis in the nucleotide-binding domain (NBD) effects conformational changes in the transmembrane domain that lead to allocrite translocation remains largely unknown. A possible aspect of this mechanism was suggested by previous molecular dynamics simulations of the MJ0796 NBD dimer, which revealed a novel, nucleotide-dependent intrasubunit conformational change involving the relative rotation of the helical and catalytic subdomains. Here, we find that in four of five simulations of the ADP/ATP-bound dimer, the relative rotation of the helical and catalytic subdomains in the ADP-bound monomer results in opening of the ADP-bound active site, probably sufficient or close to sufficient to allow nucleotide exchange. We also observe that in all five simulations of the ADP/ATP-bound dimer, the intimate contact of the LSGGQ signature sequence with the ATP gamma-phosphate is weakened by the intrasubunit conformational change within the ADP-bound monomer. We discuss how these results support a constant contact model for the function of the NBD dimer in contrast to switch models, in which the NBDs are proposed to fully disassociate during the catalytic cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / chemistry*
  • ATP-Binding Cassette Transporters / metabolism*
  • Adenosine Diphosphate / chemistry
  • Adenosine Diphosphate / metabolism*
  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism*
  • Catalytic Domain
  • Computer Simulation
  • Crystallography, X-Ray
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization
  • Protein Structure, Tertiary

Substances

  • ATP-Binding Cassette Transporters
  • Adenosine Diphosphate
  • Adenosine Triphosphate