title: The NorM MATE transporter from N. gonorrhoeae: insights into drug and ion binding from atomistic molecular dynamics simulations.
abstract: The multidrug and toxic compound extrusion transporters extrude a wide variety of substrates out of both mammalian and bacterial cells via the electrochemical gradient of protons and cations across the membrane. The substrates transported by these proteins include toxic metabolites and antimicrobial drugs. These proteins contribute to multidrug resistance in both mammalian and bacterial cells and are therefore extremely important from a biomedical perspective. Although specific residues of the protein are known to be responsible for the extrusion of solutes, mechanistic details and indeed structures of all the conformational states remain elusive. Here, we report the first, to our knowledge, simulation study of the recently resolved x-ray structure of the multidrug and toxic compound extrusion transporter, NorM from Neisseria gonorrhoeae (NorM_NG). Multiple, atomistic simulations of the unbound and bound forms of NorM in a phospholipid lipid bilayer allow us to identify the nature of the drug-protein/ion-protein interactions, and secondly determine how these interactions contribute to the conformational rearrangements of the protein. In particular, we identify the molecular rearrangements that occur to enable the Na(+) ion to enter the cation-binding cavity even in the presence of a bound drug molecule. These include side chain flipping of a key residue, GLU-261 from pointing toward the central cavity to pointing toward the cation binding side when bound to a Na(+) ion. Our simulations also provide support for cation binding in the drug-bound and apo states of NorM_NG.
authors.affiliation: School of Chemistry, University of Southampton, Highfield, Southampton, United Kingdom.
authors.forename: Yuk Ming
authors.initials: YM
authors.lastname: Leung
authors.affiliation: School of Chemistry, University of Southampton, Highfield, Southampton, United Kingdom.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Holdbrook
authors.affiliation: School of Chemistry, University of Southampton, Highfield, Southampton, United Kingdom.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Piggot
authors.affiliation: School of Chemistry, University of Southampton, Highfield, Southampton, United Kingdom. Electronic address: s.khalid@soton.ac.uk.
authors.forename: Syma
authors.initials: S
authors.lastname: Khalid
mesh_terms: D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000494:pharmacology*; D017920:Antiporters / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D008051:Lipid Bilayers / Q000737:chemistry; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009344:Neisseria gonorrhoeae / Q000737:chemistry*; D011485:Protein Binding; D012964:Sodium / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D017920:Antiporters; D001426:Bacterial Proteins; D008051:Lipid Bilayers; C114619:NorM protein, bacteria; D012964:Sodium