We present a discovery pipeline integrating chemical fragment screening and time-resolved, high-throughput small-angle X-ray scattering (TR-HT-SAXS). This approach identifies allosteric chemical leads targeting distinct allosteric states of the mitochondrial oxidoreductase apoptosis-inducing factor (AIF). By monitoring kinetic rates of allosteric transition with TR-HT-SAXS, we link fragment structure–activity relationships (SARs) to biomolecular conformation.
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References
Brosey, C. A. & Tainer, J. A. Evolving SAXS versatility: solution X-ray scattering for macromolecular architecture, functional landscapes, and integrative structural biology. Curr. Opin. Struct. Biol. 58, 197–213 (2019). A review article presenting an overview of SAXS and its applications.
Brosey, C. A. et al. Defining NADH-driven allostery regulating apoptosis-inducing factor. Structure 24, 2067–2079 (2016). This study reports structural determinants of AIF allosteric states.
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This is a summary of: Brosey, C. A. et al. Chemical screening by time-resolved X-ray scattering to discover allosteric probes. Nat. Chem. Biol. https://doi.org/10.1038/s41589-024-01609-1 (2024).
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Time-resolved HT-SAXS discovers allosteric chemotypes for redox target AIF. Nat Chem Biol (2024). https://doi.org/10.1038/s41589-024-01610-8
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DOI: https://doi.org/10.1038/s41589-024-01610-8
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