Person: Coote, Paul
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Coote
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Paul
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Coote, Paul
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Publication Allosteric Sensitization of Pro-Apoptotic BAX(2017) Pritz, Jonathan R.; Wachter, Franziska; Lee, Susan; Luccarelli, James; Wales, Thomas E.; Cohen, Daniel; Coote, Paul; Heffron, Gregory; Engen, John R.; Massefski, Walter; Walensky, LorenBAX is a critical apoptotic regulator that can be transformed from a cytosolic monomer into a lethal mitochondrial oligomer, yet drug strategies to modulate it are underdeveloped due to longstanding difficulties in conducting screens on this aggregation-prone protein. Here, we overcame prior challenges and performed an NMR-based fragment screen of full-length human BAX. We identified a compound that sensitizes BAX activation by binding to a pocket formed by the junction of the α3/α4 and α5/α6 hairpins. Biochemical and structural analyses revealed that the molecule sensitizes BAX by allosterically mobilizing the α1–α2 loop and BAX BH3 helix, two motifs implicated in the activation and oligomerization of BAX, respectively. By engaging a region of core hydrophobic interactions that otherwise preserve the BAX inactive state, the identified compound informs fundamental mechanisms for conformational regulation of BAX and provides a new opportunity to reduce the apoptotic threshold for potential therapeutic benefit.Publication Mixed pyruvate labeling enables backbone resonance assignment of large proteins using a single experiment(Nature Publishing Group UK, 2018) Robson, Scott; Takeuchi, Koh; Boeszoermenyi, Andras; Coote, Paul; Dubey, Abhinav; Hyberts, Sven; Wagner, Gerhard; Arthanari, HaribabuBackbone resonance assignment is a critical first step in the investigation of proteins by NMR. This is traditionally achieved with a standard set of experiments, most of which are not optimal for large proteins. Of these, HNCA is the most sensitive experiment that provides sequential correlations. However, this experiment suffers from chemical shift degeneracy problems during the assignment procedure. We present a strategy that increases the effective resolution of HNCA and enables near-complete resonance assignment using this single HNCA experiment. We utilize a combination of 2-13C and 3-13C pyruvate as the carbon source for isotope labeling, which suppresses the one bond (1Jαβ) coupling providing enhanced resolution for the Cα resonance and amino acid-specific peak shapes that arise from the residual coupling. Using this approach, we can obtain near-complete (>85%) backbone resonance assignment of a 42 kDa protein using a single HNCA experiment.Publication Design of Mixing Pulses for NMR Spectroscopy by Repeated Rotating Frames(2014-06-06) Coote, Paul; Wagner, Gerhard; Khaneja, Navin; Brockett, Roger; Lu, YueIn protein NMR spectroscopy, homonuclear mixing pulses are used to reveal correlations amongst chemically bonded nuclear spins.