8ABX
Crystal structure of IDO1 in complex with Apoxidole-1
Summary for 8ABX
| Entry DOI | 10.2210/pdb8abx/pdb |
| Descriptor | Indoleamine 2,3-dioxygenase 1, TETRAETHYLENE GLYCOL, TRIETHYLENE GLYCOL, ... (6 entities in total) |
| Functional Keywords | heme-binding protein, natural product, indoleamine 2, 3-dioxygenase 1, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 47545.67 |
| Authors | Dotsch, L.,Ziegler, S.,Waldmann, H.,Gasper, R. (deposition date: 2022-07-05, release date: 2022-08-24, Last modification date: 2024-01-31) |
| Primary citation | Davies, C.,Dotsch, L.,Ciulla, M.G.,Hennes, E.,Yoshida, K.,Gasper, R.,Scheel, R.,Sievers, S.,Strohmann, C.,Kumar, K.,Ziegler, S.,Waldmann, H. Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype. Angew.Chem.Int.Ed.Engl., 61:e202209374-e202209374, 2022 Cited by PubMed Abstract: Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole- and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research. PubMed: 35959923DOI: 10.1002/anie.202209374 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.65 Å) |
Structure validation
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