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Multidrug Transport

McKeegan et al 2003 Review: we still arent sure how pumps interact with substrates. 2 drug binding sites either side of the membrane alternately exposed with the shift due to ATP. TetR is a drug binding repressor of genes, released in presence of tetracycline.
Paulsen 2003 (only author) Review: Wide spec of efflux pumps due to flexible hydrophobic binding pockets. 5 known families. AcrB is E.coli, has windows to the periplasm and takers drug from there (other pumps dont). MsbA (E.coli) is an ABC clears the cyt membrane to remove lipids
Van Veen 2010 (only author) Presence of a large,flexible binding surface in MATE family transporters necessitates big conformational changes and thus slows the mechanism. Commenting on He 2010
He et al 2010 X-ray crystal of the NorM MATE transporter from vib. cholerae. Has windows into the leaflet. Use Na or H gradients to power the pump. Scissors type opening, outward facing has high cation affinity but low substrate affinity, reversed in inward facing.
Gutmann et al 2010 Review: ABC transporters use dimeric NBDs to hydrolyse ATP. QacR is an s.aureus regulatory protein able to bind compounds in at least 2 orientations. Homology with ABCB1 & LmrA transporters, tm helics seem to rotate 90deg from high to low affinity sites.
Higgins & Gottesman 1992 Review: Refers to ABC transporters. These are able to protect even against drugs with high affinity (suggests the drugs arent getting close). Proposed inner leaflet clearance either to the outer leaflet or out of the cell. ABCs prefer lipophilic drugs.
Shapiro et al 1997 Showed that incr pump activity removed hoechst33342 from the membrane, only fluoresces in the membrane. Low membrane volume so lipophilic drugs accumulate at v. high concentrations. Lack of self quenching shows drug isnt being flipped, removed instead
Ryu et al 2000 MRP2 is ATP dependent pump, homology with P-glycoprotein. Secretes conjugates with glutathione, sulphate etc which are made by liver. Charged residues in tm domains are vital for transport (mutated each residue in turn to an arginine). MRP1 is similar
Zhang et al 2001 Murine MRP1 (unlike human) cannot confer anthracycline resistance. Converting glutamine to glutamate allowed resistance, first identified the rough area of critical amino acids by mutating chunks. Anthracyclines are cationic, -ve charged amino acid helps
Zheleznova et al 1999 Binding to BmrR (reg protein) is mediated by stacking interaction and electrostatic bind to glutamate. C-terminus was not homologous to other regulators so thought to be drug binding site, crystallised it. alpha2 helix folding reqd for drug binding.
Higgins 2007 (only author) Review: ABC: Clear inner leaflet, single binding site. RND: often use proton gradient, req TolC pore, peristaltic clearance of periplasm. SMR: alternating access coupled to protons. MFS: Large cavity, one binding site with alternating access, proton p
Woebking et al 2008 Superimposed ABCB1 specificity changing mutations onto homologous MsbA. Taxol binding reduced in SASA mutant (2 serine to alanine in tm6). Ethidium binding also decr, although it doesnt compete with taxol for wt transport, close but non-overlapping sites.
Hall et al 2009 Review: Resistant cancer cells often hypersensitive to other drugs due to upreg of compensatory enzymes. P-glycoprotein inhibited by verapamil which incr ATP usage to toxic levels generating ROS, only works when p-gp upregulated.
Han 2000 (only author) Review: prodrugs. May be added to polar nutrient for removal at brush border (or BBB) to deliver non-polar drug. May be activated by microflora of a certain gut stage. We can give the prodrug with activating enzymes conjugated to tumour antibodies.
Seelig & Landwojtowicz 2000 Shows membrane partitioning is the rate limiting step in p-glycoprotein drug removal. Hydrogen bonds mediate binding of drug to transporter and thus inhibit transport of compounds with fewer hydrogen bonds.
Edgar & Bibi 1999 Replacement of a charged residue (glutamate) in the tm domain of an ABC transporter (MdfA) alters that transporter's specificity, preventing transport of lipophilic cations. Replaced with arg (neut), lys (+ve) and aspartate (-ve but small).
Ward et al 2007 Open structure of MsbA (ABC trans), possible communication between NBD and TMD. Substrate is predicted to bind the 'hinge' region with alternating access. NBDs seem to come together to hydrolyse ATP. Upside-down V has an open cavity at inner leaflet level
Dawson et al 2006 Closed structure of sav1866 (ABC trans). Required Ward 2007 to show the shift to open. Showed NBDs together, with binding site open to extracellular region. ATP binding closes the channel to the cell, hydrolysis exposes the binding site again.
Murakami et al 2002 Shows AcrB (RND transporter) structure with peristaltic motion. Trimeric. Clears the membrane with direct access to outer leaflet, also thought to access inner leaflet and periplasm. Couples to TolC
Murakami et al 2006 Each unit of AcrB (RND) trimer is at different phase, binding site is flexible and uses stacked aromatic residues. Confirms peristaltic motion with 3 sequential stages
Pawagi et al 1994 First indication that aromatic residues may be involved in drug binding as they are conserved in tm domains of transporters. Modelled the domains based on the sequence of p-glycoprotein.
Ito et al 2001 Shows that mutation of the conserved aromatic residues in the transmembrane domain is able to alter transporter specificity. used MRP1 (ABC)
Garrigues et al 2002 Generated two pharmacophores for p-glycoprotein based on drugs known to bind. The two pharmacophores showed partial overlap, presumably neither fits the full binding site. Pharmacophores handy as perfect pump substrates can cause expensive futile cycles
Doshi et al 2010 Mutated 2 residues of an ABC transporter which were known to approximate in the inward facing state to cysteine and showed that dimerisation was reduced by unhydrolysable ATP, showing that ATP binding led to the outward facing conformation
Created by: Jonmassie



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