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.
Brosey, C. A. et al. Applying HT-SAXS to chemical ligand screening. Methods Enzymol. 678, 331–350 (2023). A protocol for preparing chemical ligand screens for SAXS analysis.
Moiani, D. et al. An efficient chemical screening method for structure-based inhibitors to nucleic acid enzymes targeting the DNA repair-replication interface and SARS CoV-2. Methods Enzymol. 661, 407–431 (2021). This methods paper describes the small-molecule library used in this study.
Hura, G. L. et al. Comprehensive macromolecular conformations mapped by quantitative SAXS analyses. Nat. Methods 10, 453–454 (2013). This paper describes the SAXS VR similarity metric used for TR-HT-SAXS.
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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
