9KJO

The mTREX1-NSC 37215 complex structure by soaking in Soaking Condition 2 (NSC 37215-1 complex 2)

これはPDB形式変換不可エントリーです。

9KJO の概要

• エントリーDOI: 10.2210/pdb9kjo/pdb
• 関連するPDBエントリー: 9KJD 9KJE 9KJF 9KJG 9KJH 9KJI 9KJJ 9KJK 9KJL 9KJM 9KJN
• 分子名称: Three-prime repair exonuclease 1, ACETATE ION, 7-[(4-benzamidophenyl)carbonylamino]-4-oxidanyl-naphthalene-2-sulfonic acid, ... (4 entities in total)
• 機能のキーワード: trex1, inhibitor, deddh exonuclease, hydrolase
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55533.91

構造登録者

Hsiao, Y.Y.,Huang, K.W.,Wu, C.Y.,Tsai, C.Y.,Wu, M.T. (登録日: 2024-11-12, 公開日: 2026-01-28)

主引用文献

Huang, K.W.,Yu Tsai, C.,Wu, C.Y.,Lin, W.C.,Wu, M.T.,Hsu, K.C.,Yu Yang, C.,Chang, I.Y.,Liu, H.M.,Chu, J.W.,Hsiao, Y.Y.
Disordered DNA-binding motif forms a modulation site for inhibiting the cancer immunotherapy target TREX1.
Nucleic Acids Res., 54:-, 2026

PubMed Abstract: In nucleic acid-binding proteins, short linear motifs (SLiMs)-an important subclass of intrinsically disordered regions (IDRs)-offer diverse opportunities for therapeutic intervention, yet their structural and functional roles remain largely elusive. Away from the active site of cancer immunotherapy target exonuclease TREX1, a novel modulation site formed by the intrinsically disordered α7-α8 loop is discovered by X-ray crystallography with newly identified inhibitors. Despite that the structure of α7-α8 loop upon binding-coupled disordered-to-ordered transition is inhibitor specific, a pattern of multivertex clamping is consistently observed. Mechanistically, the fuzzy TREX1-inhibitor interactions elucidated by structural analysis and molecular dynamics simulations reveal an ensemble of chemical-scale amphiphilic units for inhibitor moieties to anchor to. Functional assays confirm that our newly identified inhibitors disrupt the DNA binding and immunosuppressive activity of TREX1, establishing α7-α8 loop as a druggable SLiM. This work provides a first collection of atomic details for small-molecule inhibition involving a DNA-binding SLiM, and the mechanistic principles uncovered here may be generalized to targeting IDRs in cancer immunotherapy.

PubMed: 41533589
DOI: 10.1093/nar/gkaf1511

実験手法

X-RAY DIFFRACTION (2 Å)