7A1S

FACTOR INHIBITING HIF-1 ALPHA IN COMPLEX WITH ZN(II), 3-methyl-2-oxoglutarate, AND TANKYRASE-2 (TNKS2) FRAGMENT PEPTIDE (21-MER)

7A1S の概要

• エントリーDOI: 10.2210/pdb7a1s/pdb
• 分子名称: Hypoxia-inducible factor 1-alpha inhibitor, TANKYRASE-2, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: hypoxia-inducible factor asparagine hydroxylase, dioxygenase, oxidoreductase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43551.72

構造登録者

Nakashima, Y.,Brewitz, L.,Schofield, C.J. (登録日: 2020-08-13, 公開日: 2021-08-25, 最終更新日: 2024-01-31)

主引用文献

Nakashima, Y.,Brewitz, L.,Tumber, A.,Salah, E.,Schofield, C.J.
2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases.
Nat Commun, 12:6478-6478, 2021

PubMed Abstract: 2-Oxoglutarate (2OG) oxygenases are validated agrochemical and human drug targets. The potential for modulating their activity with 2OG derivatives has not been explored, possibly due to concerns regarding selectivity. We report proof-of-principle studies demonstrating selective enhancement or inhibition of 2OG oxygenase activity by 2-oxo acids. The human 2OG oxygenases studied, factor inhibiting hypoxia-inducible transcription factor HIF-α (FIH) and aspartate/asparagine-β-hydroxylase (AspH), catalyze C3 hydroxylations of Asp/Asn-residues. Of 35 tested 2OG derivatives, 10 enhance and 17 inhibit FIH activity. Comparison with results for AspH reveals that 2OG derivatives selectively enhance or inhibit FIH or AspH. Comparison of FIH structures complexed with 2OG derivatives to those for AspH provides insight into the basis of the observed selectivity. 2-Oxo acid derivatives have potential as drugs, for use in biomimetic catalysis, and in functional studies. The results suggest that the in vivo activity of 2OG oxygenases may be regulated by natural 2-oxo acids other than 2OG.

PubMed: 34759269
DOI: 10.1038/s41467-021-26673-2

実験手法

X-RAY DIFFRACTION (2.01 Å)