9s1u

Crystal structure of human IDO1 in complex with iDeg-3

spinqualitylabelsall models 9s1u, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9s1u is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2Å Ligands: A1JLE, PEG, PG4, PGE, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function I23O1_HUMAN Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen. Publication Abstract from PubMed Terpenoid alkaloids are derived from the fusion of structurally diverse terpenoid- and alkaloid moieties. The biologically relevant chemical space defined by this unique natural product (NP) class may be explored beyond the limitations of biosynthetic pathways by means of the pseudo natural product (PNP) principle, i.e., by combination of NP fragments in different arrangements. We describe the design, synthesis and structural evolution of a monoterpene-pyrrolidine PNP collection obtained by functionalization and combination of bicyclic monoterpenes with pyrrolidine alkaloid-derived fragments. Diverse fusion strategies led to the discovery of (-)-myrtenal-pyrrolidine PNPs that are indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors and degraders, termed iDegs. Structural fine-tuning modulated both degradation and inhibition potencies. Co-crystallization revealed that iDegs induce unprecedented changes in the C-terminus of IDO1 which promote degradation. iDegs inhibited tumor growth in SKOV-3 tumor-bearing mice and led to prolonged survival, which promises to inspire novel medicinal chemistry programs aimed at IDO1 in different diseases. Design, Synthesis, and Structural Evolution of Pseudo-Natural Product IDO1 Inhibitors and Degraders.,Cheng XF, Lucas B, Lampe P, Ugel S, Chen S, Unger A, Bischoff M, Adariani SR, Naredla KR, Kumar K, Schmidt A, Strohmann C, Janning P, Gasper R, Lucas M, Gersch M, Sievers S, Bronte V, Ziegler S, Waldmann H Angew Chem Int Ed Engl. 2025 Nov 27:e18753. doi: 10.1002/anie.202518753. PMID:41310997 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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