8D3I

Crystal structure of human Apoptosis-Inducing Factor (AIF) W196A mutant complexed with quinolin-4-amine

Summary for 8D3I

• Entry DOI: 10.2210/pdb8d3i/pdb
• Descriptor: Apoptosis-inducing factor 1, mitochondrial, quinolin-4-amine, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: oxidoreductase, mitochondrial import, oxidative phosphorylation, saxs
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 120936.57

Authors

Brosey, C.A.,Tainer, J.A. (deposition date: 2022-06-01, release date: 2023-11-08, Last modification date: 2024-05-29)

Primary citation

Brosey, C.A.,Link, T.M.,Shen, R.,Moiani, D.,Burnett, K.,Hura, G.L.,Jones, D.E.,Tainer, J.A.
Chemical screening by time-resolved X-ray scattering to discover allosteric probes.
Nat.Chem.Biol., 2024

PubMed Abstract: Drug discovery relies on efficient identification of small-molecule leads and their interactions with macromolecular targets. However, understanding how chemotypes impact mechanistically important conformational states often remains secondary among high-throughput discovery methods. Here, we present a conformational discovery pipeline integrating time-resolved, high-throughput small-angle X-ray scattering (TR-HT-SAXS) and classic fragment screening applied to allosteric states of the mitochondrial import oxidoreductase apoptosis-inducing factor (AIF). By monitoring oxidized and X-ray-reduced AIF states, TR-HT-SAXS leverages structure and kinetics to generate a multidimensional screening dataset that identifies fragment chemotypes allosterically stimulating AIF dimerization. Fragment-induced dimerization rates, quantified with time-resolved SAXS similarity analysis (k), capture structure-activity relationships (SAR) across the top-ranked 4-aminoquinoline chemotype. Crystallized AIF-aminoquinoline complexes validate TR-SAXS-guided SAR, supporting this conformational chemotype for optimization. AIF-aminoquinoline structures and mutational analysis reveal active site F482 as an underappreciated allosteric stabilizer of AIF dimerization. This conformational discovery pipeline illustrates TR-HT-SAXS as an effective technology for targeting chemical leads to important macromolecular states.

PubMed: 38671223
DOI: 10.1038/s41589-024-01609-1

Experimental method

X-RAY DIFFRACTION (2.65 Å)