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Full-Text Articles in Life Sciences
Leveraging Local Perturbations To Map Allosteric Networks Of Phosphatases, Tamar (Skaist) Mehlman
Leveraging Local Perturbations To Map Allosteric Networks Of Phosphatases, Tamar (Skaist) Mehlman
Dissertations, Theses, and Capstone Projects
Allostery is central to regulation of protein function, but our mechanistic understanding remains incomplete. A deeper understanding of how redistributions of conformational states drive allostery in proteins could allow us to better grasp natural regulatory principles in cells and open new doors to therapeutic development. Conformationally dynamic human Protein Tyrosine Phosphatases (PTPs) exemplify the challenges and opportunities associated with allostery. The archetypal PTP, PTP1B, has been highly validated as a therapeutic target but no allosteric inhibitors have been approved for clinical use. This is largely because our understanding of the mechanisms underlying allostery in PTP1B remains limited, despite the discovery …
Supercharged Models Of Intrinsically Disordered Proteins And Their Utility In Sensing, Peter J. Schnatz
Supercharged Models Of Intrinsically Disordered Proteins And Their Utility In Sensing, Peter J. Schnatz
Dissertations, Theses, and Capstone Projects
In this thesis I show that greatly increasing the magnitude of a protein’s net charge using surface supercharging transforms that protein into a ligand-gated or counterion-gated conformational molecular switch. To demonstrate this I first modified the designed helical bundle hemoprotein H4 using simple molecular modeling, creating a highly charged protein which both unfolds reversibly at low ionic strength and undergoes the ligand-induced folding transition commonly observed in signal transduction by intrinsically disordered proteins in biology. Due to the high surface charge density, ligand binding to this protein is allosterically activated by low concentrations of divalent cations and the polyamine spermine. …
Journey To The Center Of The Protein: Allostery From Multitemperature Multiconformer X-Ray Crystallography, Daniel A. Keedy
Journey To The Center Of The Protein: Allostery From Multitemperature Multiconformer X-Ray Crystallography, Daniel A. Keedy
Advanced Science Research Center
Proteins inherently fluctuate between conformations to perform functions in the cell. For example, they sample product-binding, transition-state-stabilizing and product-release states during catalysis, and they integrate signals from remote regions of the structure for allosteric regulation. However, there is a lack of understanding of how these dynamic processes occur at the basic atomic level. This gap can be at least partially addressed by combining variable-temperature (instead of traditional cryogenic temperature) X-ray crystallography with algorithms for modeling alternative conformations based on electron-density maps, in an approach called multitemperature multiconformer X-ray crystallography (MMX). Here, the use of MMX to reveal alternative conformations at …