Thomas E. Wales

Thermodynamic Insights into the WT and Y220C TP53 DBDs Reveal that the Oncogenic Y220C Variant is a Loss-of-Function Mutation for Zn2+-Binding at Physiological Temperature

Jacob I. Stuckey, Valérie Vivat, Bradley M. Dickson, Jeremy W. Setser et autres

Abstract We present evidence of previously unrecognized allosteric connectivity across the TP53 DNA-binding domain (DBD). Specifically, we have found evidence of an explicit influence on the Zn2+-binding site from the region surrounding the hotspot Y220C mutation. This allosteric connectivity is intertwined with …

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An enantioselective covalent inhibitor of BAX confers cytoprotection in vivo

Peiwen Shi, Bruno Melillo, Matthew W. McHenry, Christina M. Camara et autres

No therapies directly block apoptosis in tissue injury or the many diseases driven by cell loss. The BCL-2 family protein BAX is a central mediator of this pathway and C126 resides within a key regulatory region where physiologic or pharmacologic ligands can …

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Mutation of charged inner pore residues reduce E. coli β clamp residency and increase sliding rates on DNA

Melissa L. Liriano, Micah J. McCauley, Shreya Ghosh, Dmitry M. Korzhnev et autres

ABSTRACT Sliding clamp proteins play central roles in DNA metabolism, including replication and repair. The ring-shaped E. coli beta clamp accommodates double-stranded DNA and serves as a platform for proteins involved in multiple DNA transactions. The inner pore of the beta clamp …

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Small Molecule Stabilization of Diverse Amyloidogenic Immunoglobulin Light Chains Revealed by Hydrogen–Deuterium Exchange Mass Spectrometry

Daniele Peterle, N. Yan, Elena S. Klimtchuk, Bindu Y. Srinivasu et autres

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Magnesium as a conformational gatekeeper of KRAS : Structural dynamics and therapeutic implications

Bindu Y. Srinivasu, Tanvi S Damerla, Alexander Stec, Zhiwei Zhou et autres

Abstract Magnesium serves as an essential cofactor for small GTPases, yet its structural role in regulating KRAS conformational dynamics and nucleotide exchange remains poorly understood. Here, we combine hydrogen–deuterium exchange mass spectrometry (HDX‐MS), native mass spectrometry, and functional assays to elucidate how …

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Structures of DnaA domain I reveal a dimer conserved across Actinomycetes

Porter K. Ellis, Bindu Y. Srinivasu, Jose Chavez Orozco, Gregory A. Wray et autres

DNA replication is a fundamental process in biology, and initiation marks a key regulatory step. In bacteria, DNA replication is initiated by the DnaA protein. DnaA exhibits multidomain architecture, consisting of an N-terminal domain I, linker region, AAA+ family ATPase cassette, and …

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Low-Temperature HILIC Provides Enhanced Separations and Stability for LC-MS-Based Metabolomics

Y Q Liu, Madison L. Jastrab, Michael Xiao, Miriam Lisci et autres

Liquid chromatography-mass spectrometry is a potent and robust tool for studying metabolism. However, conventional workflows can suffer from poor peak shapes, limited pressure tolerance, coelution of polar metabolites, and unstable retention times. Here, we describe the development of a more stable HILIC …

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More than an attachment module: covalent inhibitor warheads influence BTK dynamics and function

R Joseph, Robert G. Britton, David Yin-wei Lin, Julien Roche et autres

ABSTRACT Covalent inhibitors are rapidly becoming the standard of care for treatment of a range of disease states. Covalent inhibitors bind irreversibly to their target using a reactive electrophile (or ‘warhead’). Acrylamide and 2-butynamide are the most commonly used cysteine targeting electrophiles. …

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Glycerol-driven TNAP activation in thermogenesis and mineralization

Mohammed F. Hussain, Shreya S Krishnan, Brittany L. Carroll, Bożena Samborska et autres

Tissue-nonspecific alkaline phosphatase (TNAP) promotes skeletal mineralization by hydrolysing pyrophosphate1 and has been linked to uncoupling protein 1 (UCP1)-independent adipocyte thermogenesis through the futile creatine cycle through phosphocreatine hydrolysis2,3. Despite TNAP’s broad physiological roles, endogenous regulators of its activity have not been …

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A druggable redox switch on SHP1 controls macrophage inflammation

Mei Ying Ng, Meredith Nicole Nix, Guangyan Du, Ivan Davidek et autres

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Magnesium as a Conformational Gatekeeper of KRAS: Structural Dynamics and Therapeutic Implications

Bindu Y. Srinivasu, Tanvi S Damerla, Alexander Stec, Zhiwei Zhou et autres

Abstract Magnesium serves as an essential cofactor for small GTPases, yet its structural role in regulating KRAS conformational dynamics and nucleotide exchange remains poorly understood. Here, we combine hydrogen–deuterium exchange mass spectrometry (HDX-MS), native mass spectrometry, and functional assays to elucidate how …

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A druggable redox switch on SHP1 controls macrophage inflammation

Mei Ying Ng, Meredith Nicole Nix, Guangyan Du, Ivan Davidek et autres

Immunological proteins are major disease targets, yet most remain undrugged. Post-translational redox modification of cysteine residues has emerged as an important mode of immune cell regulation, particularly in macrophage cytokine responses. Here, we develop a strategy for systematic discovery and small-molecule functionalization …

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