Dr. Nate Traaseth
Department of Chemistry,New York University
“Structural Studies of Small Multidrug Resistance Membrane Proteins by Oriented and Magic-Angle-Spinning Solid-State NMR Spectroscopy in Lipid Bilayers”
Multidrug resistance (MDR) is a pervasive clinical problem that reduces the effectiveness of treatment against bacterial infections, viral infections, and cancer. Efflux of drugs across the lipid bilayer by MDR membrane protein transporters is one way in which resistance is conferred to the host organism or cell. To derive a structure/function relationship for this class of proteins, our study uses the small multidrug resistance (SMR) family as a model system for deciphering the mechanism of transport with the long-term goal of decoding the evolutionary importance of the transporter family. We used solid-state NMR (SSNMR) spectroscopy to study the topology and structure of EmrE in liposomes (magic-angle-spinning or MAS) and magnetically aligned lipid bilayers (oriented SSNMR or O-SSNMR). The MAS experiments were used to map chemical shift perturbations upon drug binding while the O-SSNMR experiments revealed the change in helix orientation upon binding and transport. Together these complementary techniques showed that drug binding perturbs both the structure of EmrE as well as the helical orientations with respect to the lipid bilayer.
Research Products Manager, Agilent Technologies
“Agilent Update from ENC and On-going Activities for NMR”
Agilent continues to invest and expand NMR technologies. With
pleasure, an update of the Agilent NMR business will be presented
along with highlights of our presentations at ENC 2012. Introduction
of new Agilent NMR personnel will also be made. And finally, in
light of the continuing economic challenges, details of several
new programs for Agilent (formerly Varian) NMR customers will also
Bristol Myers Squibb
“Characterization of ligand binding to a G-protein coupled receptor”
Reductive methylation of lysine residues permitted the introduction
of 13C-labels in samples of β2 adrenergic receptor – a member
of an important class of drug discovery targets - the G protein
coupled receptors. Indirect detection of 13C-methylated lysine
residues enabled monitoring of ligand-induced modulations of the
salt bridge between lys305 & asp192 at the interface of the
extra-cellular loops 2 & 3. This salt bridge contributes to the
formation of a cavity on the extra cellular surface of the receptor.
The extra-cellular surface adjacent to this NMR-detectable K305 :
D192 salt bridge may be amenable to the design of subtype-specific
exosite modulators of β2 AR activity, and may prove an attractive
venue for overcoming the challenge of designing subtype specific
β2 AR modulators. Distinction between highly mobile and structurally
restrained lysine methyls was achieved via saturation transfer
filtered hc hmqc and hc hsqc experiments.
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