Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase

Ariel Lewis-Ballester, Khoa N. Pham, Dipanwita Batabyal, Shay Karkashon, Jeffrey B. Bonanno, Thomas L. Poulos, Syun-Ru Yeh

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si). Structure-guided mutation of a critical residue, F270, to glycine perturbs the Si site, allowing structural determination of an inhibitory complex, where both the Sa and Si sites are occupied by Trp. The Si site offers a novel target site for allosteric inhibitors and a molecular explanation for the previously baffling substrate-inhibition behavior of the enzyme. Taken together, the data open exciting new avenues for structure-based drug design.

Original languageEnglish (US)
Article number1693
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
inhibitors
Binding Sites
Allosteric Site
Drug Design
drugs
Substrates
Glycine
effectors
Catalytic Domain
Ethanol
indoles
mutations
glycine
Pharmaceutical Preparations
Mutation
escape
enzymes
ethyl alcohol
Enzymes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase. / Lewis-Ballester, Ariel; Pham, Khoa N.; Batabyal, Dipanwita; Karkashon, Shay; Bonanno, Jeffrey B.; Poulos, Thomas L.; Yeh, Syun-Ru.

In: Nature Communications, Vol. 8, No. 1, 1693, 01.12.2017.

Research output: Contribution to journalArticle

Lewis-Ballester, Ariel ; Pham, Khoa N. ; Batabyal, Dipanwita ; Karkashon, Shay ; Bonanno, Jeffrey B. ; Poulos, Thomas L. ; Yeh, Syun-Ru. / Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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