6AZV

IDO1/BMS-978587 crystal structure

Summary for 6AZV

• Entry DOI: 10.2210/pdb6azv/pdb
• Related: 6azu
• Descriptor: Indoleamine 2,3-dioxygenase 1, (1R,2S)-2-(4-[bis(2-methylpropyl)amino]-3-{[(4-methylphenyl)carbamoyl]amino}phenyl)cyclopropane-1-carboxylic acid (3 entities in total)
• Functional Keywords: ido1 heme-displaced ligand-bound, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytosol : P14902
• Total number of polymer chains: 4
• Total formula weight: 182770.25

Authors

Lewis, H.A. (deposition date: 2017-09-13, release date: 2018-03-21, Last modification date: 2024-10-23)

Primary citation

Nelp, M.T.,Kates, P.A.,Hunt, J.T.,Newitt, J.A.,Balog, A.,Maley, D.,Zhu, X.,Abell, L.,Allentoff, A.,Borzilleri, R.,Lewis, H.A.,Lin, Z.,Seitz, S.P.,Yan, C.,Groves, J.T.
Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form.
Proc. Natl. Acad. Sci. U.S.A., 115:3249-3254, 2018

PubMed Abstract: For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to -formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme-heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor-enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.

PubMed: 29531094
DOI: 10.1073/pnas.1719190115

Experimental method

X-RAY DIFFRACTION (2.755 Å)