title: A kinetic model for the action of a resistance efflux pump.
abstract: ArsA is the catalytic subunit of the arsenical pump, coupling ATP hydrolysis to the efflux of arsenicals through the ArsB membrane protein. It is a paradigm for understanding the structure-function of the nucleotide binding domains (NBD) of medically important efflux pumps, such as P-glycoprotein, because it has two sequence-related, interacting NBD, for which the structure is known. On the basis of a rigorous analysis of the pre-steady-state kinetics of nucleotide binding and hydrolysis, we propose a model in which ArsA alternates between two mutually exclusive conformations as follows: the ArsA(1) conformation in which the A1 site is closed but the A2 site open; and the ArsA(2) conformation, in which the A1 and A2 sites are open and closed, respectively. Antimonite elicits its effects by sequestering ArsA in the ArsA(1) conformation, which catalyzes rapid ATP hydrolysis at the A2 site to drive ArsA between conformations that have high (nucleotide-bound ArsA) and low affinity (nucleotide-free ArsA) for Sb(III). ArsA potentially utilizes this process to sequester Sb(III) from the medium and eject it into the channel of ArsB.
authors.affiliation: Division of Infection and Immunity, the Institute of Biomedical and Life Sciences, Robertson Building, The University of Glasgow, Glasgow G11 6NU, Scotland, United Kingdom. A.Walmsley@bio.gla.ac.uk
authors.forename: A R
authors.initials: AR
authors.lastname: Walmsley
authors.forename: T
authors.initials: T
authors.lastname: Zhou
authors.forename: M I
authors.initials: MI
authors.lastname: Borges-Walmsley
authors.forename: B P
authors.initials: BP
authors.lastname: Rosen
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism*; D000965:Antimony / Q000378:metabolism; D053501:Arsenite Transporting ATPases; D016623:Ion Pumps; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism; D009097:Multienzyme Complexes; D010710:Phosphates / Q000378:metabolism
chemical_list: D016623:Ion Pumps; D009097:Multienzyme Complexes; D010710:Phosphates; D000244:Adenosine Diphosphate; D000965:Antimony; D000251:Adenosine Triphosphatases; D053501:Arsenite Transporting ATPases; D008274:Magnesium