Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/53789
Title: CONFORMATIONAL DYNAMICS AND ALLOSTERY IN SIGNALING PROTEINS: MONITORING TRANSIENT STATES BY STRUCTURAL MASS SPECTROMETRY
Authors: SRINATH KRISHNAMURTHY
Keywords: Chemical biology, signaling, protein dynamics, Structural mass spectrometry
Issue Date: 24-Jan-2014
Source: SRINATH KRISHNAMURTHY (2014-01-24). CONFORMATIONAL DYNAMICS AND ALLOSTERY IN SIGNALING PROTEINS: MONITORING TRANSIENT STATES BY STRUCTURAL MASS SPECTROMETRY. ScholarBank@NUS Repository.
Abstract: Proteins involved in signaling cascades are characteristic for their ability to respond to upstream stimuli and propagate these signals to downstream effector sites. Signal propagation necessitates large scale conformational changes in proteins, an inherent dynamic property of signaling proteins. How such proteins toggle between multiple conformations (conformational dynamics) is therefore fundamental in correlating protein structure with function. In this study, I aim to probe the conformational dynamics and allosteric relays in proteins populating transient transition states using structural mass spectrometry, specifically amide hydrogen/deuterium exchange mass spectrometry (HDXMS). In the first part of this study, we have uncovered allosteric relays in the activation phase of Protein Kinase A- mediated cAMP signaling pathway and highlight the active role played by cyclic nucleotide phosphodiesterases (PDEs) in signal termination. My research allowed a mapping of protein-protein (PKA-PDE) and protein-ligand (PKA-cAMP) interaction interfaces, monitor protein conformation changes in phosphodiesterase catalyzed enzymatic reactions and provide unique insights into the role of channeling in second messenger cAMP signaling. Dynamics and kinetic analysis of protein-ligand interactions in the cAMP pathway were then used to develop a novel application for HDXMS in screening low-affinity ligands (Fragments) against important target proteins. In the final part of this study I have applied HDXMS to probe conformational dynamics in large macromolecular assemblies, namely protein-DNA interactions and in virus maturation.
URI: http://scholarbank.nus.edu.sg/handle/10635/53789
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