8I7L

Crystal structure of indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with a novel inhibitor

Summary for 8I7L

• Entry DOI: 10.2210/pdb8i7l/pdb
• Descriptor: Indoleamine 2,3-dioxygenase 1, THIOSULFATE, 1-[3-[(4-chloranyl-2-fluoranyl-phenyl)carbamoylamino]-4-[cyclohexyl(2-methylpropyl)amino]phenyl]pyrrole-2-carboxylic acid, ... (4 entities in total)
• Functional Keywords: inhibitor, metal binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 91934.61

Authors

Li, K.,Liu, W.,Dong, X. (deposition date: 2023-02-01, release date: 2023-02-15, Last modification date: 2024-10-16)

Primary citation

Liu, W.,Zou, Y.,Li, K.,Zhong, H.,Yu, L.,Ge, S.,Lai, Y.,Dong, X.,Xu, Q.,Guo, W.
Apo-Form Selective Inhibition of IDO for Tumor Immunotherapy.
J Immunol., 209:180-191, 2022

PubMed Abstract: The pharmacological inhibition of IDO1 is considered an effective therapeutic approach for cancer treatment. However, the inadequate response of existing holo-IDO1 inhibitors and unclear biomarkers available in clinical practice limit the possibility of developing efficacious IDO1 inhibitors. In the current study, we aimed to elucidate the activity and mechanism of a potent 1-pyrrole-2-carboxylic acid derivative (B37) targeting apo-IDO1 and to determine its role in tumor therapy. By competing with heme for binding to apo-IDO1, B37 potently inhibited IDO1 activity, with an IC of 22 pM assessed using a HeLa cell-based assay. The x-ray cocrystal structure of the inhibitor-enzyme complex showed that the B37-human IDO1 complex has strong hydrophobic interactions, which enhances its binding affinity, determined using isothermal titration calorimetry. Stronger noncovalent interactions, including π stacking and hydrogen bonds formed between B37 and apo-human IDO1, underlay the enthalpy-driven force for B37 for binding to the enzyme. These binding properties endowed B37 with potent antitumor efficacy, which was confirmed in a mouse colon cancer CT26 syngeneic model in BALB/c mice and in an azoxymethane/dextran sulfate sodium-induced colon carcinogenesis model in C57BL/6 mice by activating the host immune system. Moreover, the combination of B37 and anti-PD1 Ab synergistically inhibited tumor growth. These results suggested that B37 may serve as a unique candidate for apo-IDO1 inhibition-mediated tumor immunotherapy.

PubMed: 35725271
DOI: 10.4049/jimmunol.2100938

Experimental method

X-RAY DIFFRACTION (2.8 Å)