6PYZ

Crystal Structure of human Tryptophan 2,3-dioxygenase in complex with PF-06840003 in Active Site

6PYZ の概要

• エントリーDOI: 10.2210/pdb6pyz/pdb
• 関連するPDBエントリー: 6PYY
• 分子名称: Tryptophan 2,3-dioxygenase, PROTOPORPHYRIN IX CONTAINING FE, (3S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione, ... (5 entities in total)
• 機能のキーワード: tryptophan dioxygenase, pf-06840003, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 184997.94

構造登録者

Pham, K.N.,Lewis-Ballester, A.,Yeh, S.R. (登録日: 2019-07-31, 公開日: 2020-01-01, 最終更新日: 2023-11-15)

主引用文献

Pham, K.N.,Lewis-Ballester, A.,Yeh, S.R.
Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase.
J.Am.Chem.Soc., 141:18771-18779, 2019

PubMed 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.

PubMed: 31682426
DOI: 10.1021/jacs.9b08871

実験手法

X-RAY DIFFRACTION (2.02 Å)