8D3J
Crystal structure of human Apoptosis-Inducing Factor (AIF) complexed with 6-fluoro-2-methylquinolin-4-amine
Summary for 8D3J
| Entry DOI | 10.2210/pdb8d3j/pdb |
| Descriptor | Apoptosis-inducing factor 1, mitochondrial, 1,2-ETHANEDIOL, FLAVIN-ADENINE DINUCLEOTIDE, ... (6 entities in total) |
| Functional Keywords | oxidoreductase, mitochondrial import, oxidative phosphorylation, saxs |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 121407.00 |
| 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 Cited by 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: 38671223DOI: 10.1038/s41589-024-01609-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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