Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase

Khoa N. Pham, Ariel Lewis-Ballester, Syun Ru Yeh

Research output: Contribution to journalArticle

Abstract

Indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are two of the only three heme-based dioxygenases in humans. They have recently been identified as key cancer immunotherapeutic drug targets. While structures of hIDO1 in complex with inhibitors have been documented, so far there are no structures of hTDO-inhibitor complexes available. Here we use PF-06840003 (IPD), a hIDO1-selective inhibitor in clinical trials, as a structural probe to elucidate inhibitor-selectivity in hIDO1 versus hTDO. Spectroscopic studies show that IPD exhibits 400-fold higher inhibition activity toward hIDO1 with respect to hTDO. Crystallographic structures reveal that the binding pocket of IPD in the active site in hIDO1 is much more flexible as compared to that in hTDO, which offers a molecular explanation for the superior inhibition activity of IPD in hIDO1 with respect to hTDO. In addition to the IPD bound in the active site, a second IPD molecule was identified in an inhibitory site on the proximal side of the heme in hIDO1 and in an exosite that is ∼40 Å away from the active site in hTDO. Taken together the data provide new insights into structure-based design of mono and dual inhibitors targeting hIDO1 and/or hTDO.

Original languageEnglish (US)
JournalJournal of the American Chemical Society
DOIs
StateAccepted/In press - Jan 1 2019

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Dioxygenases
Tryptophan
Molecules
Catalytic Domain
Heme
Indoleamine-Pyrrole 2,3,-Dioxygenase
human indoleamine 2,3-dioxygenase 1
Clinical Trials

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase. / Pham, Khoa N.; Lewis-Ballester, Ariel; Yeh, Syun Ru.

In: Journal of the American Chemical Society, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "Indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are two of the only three heme-based dioxygenases in humans. They have recently been identified as key cancer immunotherapeutic drug targets. While structures of hIDO1 in complex with inhibitors have been documented, so far there are no structures of hTDO-inhibitor complexes available. Here we use PF-06840003 (IPD), a hIDO1-selective inhibitor in clinical trials, as a structural probe to elucidate inhibitor-selectivity in hIDO1 versus hTDO. Spectroscopic studies show that IPD exhibits 400-fold higher inhibition activity toward hIDO1 with respect to hTDO. Crystallographic structures reveal that the binding pocket of IPD in the active site in hIDO1 is much more flexible as compared to that in hTDO, which offers a molecular explanation for the superior inhibition activity of IPD in hIDO1 with respect to hTDO. In addition to the IPD bound in the active site, a second IPD molecule was identified in an inhibitory site on the proximal side of the heme in hIDO1 and in an exosite that is ∼40 {\AA} away from the active site in hTDO. Taken together the data provide new insights into structure-based design of mono and dual inhibitors targeting hIDO1 and/or hTDO.",
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