9EZJ

Apo human TDO in complex with a bound inhibitor (Cpd-4)

これはPDB形式変換不可エントリーです。

9EZJ の概要

• エントリーDOI: 10.2210/pdb9ezj/pdb
• 分子名称: Tryptophan 2,3-dioxygenase, alpha-methyl-L-tryptophan, ethyl (9~{R})-2-methoxy-4-oxidanylidene-9-[[(1~{S})-1-phenylethyl]-[(2-propan-2-ylphenyl)carbamoyl]amino]-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-3-carboxylate, ... (4 entities in total)
• 機能のキーワード: apo-tdo, heme, inhibitor, oxidoreductase
• 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: 193992.05

構造登録者

Wicki, M.,Mac Sweeney, A. (登録日: 2024-04-12, 公開日: 2024-06-05, 最終更新日: 2024-11-27)

主引用文献

Lotz-Jenne, C.,Lange, R.,Cren, S.,Bourquin, G.,Goglia, L.,Kimmerlin, T.,Wicki, M.,Muller, M.,Artico, N.,Ackerknecht, S.,Pfaff, P.,Joesch, C.,Mac Sweeney, A.
Discovery and binding mode of small molecule inhibitors of the apo form of human TDO2.
Sci Rep, 14:27937-27937, 2024

PubMed Abstract: Tryptophan-2,3-dioxygenase (TDO2) and indoleamine-2,3-dioxygenase (IDO1) are structurally distinct heme enzymes that catalyze the conversion of L-tryptophan to N-formyl-kynurenine, and play important roles in metabolism, inflammation, and tumor immune surveillance. The enzymes can adopt an inactive, heme-free (apo) state or an active, heme-containing (holo) state, with the balance between them varying dynamically according to biological conditions. Inhibitors of holo-TDO2 are known but, despite several advantages of the heme-free state as a drug target, no inhibitors of apo-TDO2 have been reported. We describe the discovery of the first apo-TDO2 binding inhibitors, to our knowledge, and their inhibition of cellular TDO2 activity at low nanomolar concentrations. The crystal structure of a potent, small molecule inhibitor bound to apo-TDO2 reveals its detailed binding interactions within the large, hydrophobic heme binding pocket of the active site.

PubMed: 39537789
DOI: 10.1038/s41598-024-78981-4

実験手法

X-RAY DIFFRACTION (2.612 Å)