Dataset Information

Mechanism of coupling drug transport reactions located in two different membranes.

ABSTRACT: Gram- negative bacteria utilize a diverse array of multidrug transporters to pump toxic compounds out of the cell. Some transporters, together with periplasmic membrane fusion proteins (MFPs) and outer membrane channels, assemble trans-envelope complexes that expel multiple antibiotics across outer membranes of Gram-negative bacteria and into the external medium. Others further potentiate this efflux by pumping drugs across the inner membrane into the periplasm. Together these transporters create a powerful network of efflux that protects bacteria against a broad range of antimicrobial agents. This review is focused on the mechanism of coupling transport reactions located in two different membranes of Gram-negative bacteria. Using a combination of biochemical, genetic and biophysical approaches we have reconstructed the sequence of events leading to the assembly of trans-envelope drug efflux complexes and characterized the roles of periplasmic and outer membrane proteins in this process. Our recent data suggest a critical step in the activation of intermembrane efflux pumps, which is controlled by MFPs. We propose that the reaction cycles of transporters are tightly coupled to the assembly of the trans-envelope complexes. Transporters and MFPs exist in the inner membrane as dormant complexes. The activation of complexes is triggered by MFP binding to the outer membrane channel, which leads to a conformational change in the membrane proximal domain of MFP needed for stimulation of transporters. The activated MFP-transporter complex engages the outer membrane channel to expel substrates across the outer membrane. The recruitment of the channel is likely triggered by binding of effectors (substrates) to MFP or MFP-transporter complexes. This model together with recent structural and functional advances in the field of drug efflux provides a fairly detailed understanding of the mechanism of drug efflux across the two membranes.

SUBMITTER: Zgurskaya HI

PROVIDER: S-EPMC4338810 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mechanism of coupling drug transport reactions located in two different membranes.

Zgurskaya Helen I HI Weeks Jon W JW Ntreh Abigail T AT Nickels Logan M LM Wolloscheck David D

Frontiers in microbiology 20150224

Gram- negative bacteria utilize a diverse array of multidrug transporters to pump toxic compounds out of the cell. Some transporters, together with periplasmic membrane fusion proteins (MFPs) and outer membrane channels, assemble trans-envelope complexes that expel multiple antibiotics across outer membranes of Gram-negative bacteria and into the external medium. Others further potentiate this efflux by pumping drugs across the inner membrane into the periplasm. Together these transporters creat ...[more]

PMID: 25759685

Similar Datasets

Project description:All-atom (AA) molecular dynamics simulations are used to unravel the binding mechanism of yeast oxysterol binding protein (Osh4) to model membranes with varying anionic lipid concentration using AA and the highly mobile membrane mimetic (HMMM) representations. For certain protein-lipid interactions, an improved forcefield description is used (CUFIX) to accurately describe lipid-protein electrostatic interactions. Our detailed computational studies have identified a single, β-crease oriented, membrane-bound conformation of Osh4 for all anionic membranes. The penetration of the PHE-239 residue below the membrane phosphate plane is the characteristic signature of the membrane-bound state of Osh4. As the phenylalanine loop anchors itself deeply in the membrane; the other regions of the Osh4, namely, ALPS motif, β6- β7 loop, β14- β15 loop, and β16- β17 loop, maximize their contact with the membrane. Furthermore, loose lipid packing and higher mobility of HMMM enable stronger association of the ALPS motif with the membrane lipids through its hydrophobic surface. After the HMMM is converted to AA and equilibrated, the binding is two to three times stronger compared with simulations started with the AA representation, yielding the major importance of the ALPS motif to binding. Quantitative estimation of binding energy revealed that the phenylalanine loop plays a crucial role in stable membrane attachment of Osh4 and contributes significantly toward overall binding process. The CUFIX parameters provide a more balanced picture of hydrophobic and electrostatic interactions between the protein and the membrane, which differs from our past work that showed salt bridges alone stabilized Osh4-membrane contact. Our study provides a comprehensive picture of the binding mechanism of Osh4 with model single membranes and, thus, understanding of the initial interactions is important for elucidating the biological function of this protein to shuttle lipids between organelles.

Dataset Information

Mechanism of coupling drug transport reactions located in two different membranes.

Publications

Mechanism of coupling drug transport reactions located in two different membranes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets