9FOH
Crystal structure of human IDO1 in complex with iDeg-2
This is a non-PDB format compatible entry.
Summary for 9FOH
| Entry DOI | 10.2210/pdb9foh/pdb |
| Descriptor | Indoleamine 2,3-dioxygenase 1, TETRAETHYLENE GLYCOL, TRIETHYLENE GLYCOL, ... (6 entities in total) |
| Functional Keywords | indoleamine 2, 3-dioxygenase 1, heme-binding protein, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 47049.12 |
| Authors | Lucas, B.,Lucas, M.,Ziegler, S.,Waldmann, H.,Gasper, R. (deposition date: 2024-06-11, release date: 2025-10-01, Last modification date: 2026-01-21) |
| Primary citation | Hennes, E.,Lucas, B.,Scholes, N.S.,Cheng, X.F.,Scott, D.C.,Bischoff, M.,Reich, K.,Gasper, R.,Lucas, M.,Xu, T.T.,Rossini, S.,Pulvermacher, L.M.,Dotsch, L.,Imrichova, H.,Brause, A.,Fuhrer, S.,Naredla, K.R.,Sievers, S.,Kumar, K.,Janning, P.,Orabona, C.,Gersch, M.,Murray, P.J.,Schulman, B.A.,Winter, G.E.,Ziegler, S.,Waldmann, H. Monovalent pseudo-natural products supercharge degradation of IDO1 by its native E3 KLHDC3. Nat.Chem., 2026 Cited by PubMed Abstract: Targeted protein degradation modulates protein function beyond the inhibition of enzyme activity or protein-protein interactions. Most degrader drugs function by directly mediating the proximity between a neosubstrate and a hijacked E3 ligase. Here we identify pseudo-natural products derived from (-)-myrtanol, termed iDegs, that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs boost IDO1 ubiquitination and degradation by the cullin-RING E3 ligase CRL2, which we identified to natively mediate ubiquitin-mediated degradation of IDO1. Therefore, iDegs increase IDO1 turnover using the native proteolytic pathway. In contrast to clinically explored IDO1 inhibitors, iDegs reduce the formation of kynurenine by both inhibition and induced degradation of the enzyme and thus also modulate the non-enzymatic functions of IDO1. This unique mechanism of action may open up alternative therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1. PubMed: 41501556DOI: 10.1038/s41557-025-02021-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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