6TLC

Unphosphorylated human STAT3 in complex with MS3-6 monobody

6TLC の概要

• エントリーDOI: 10.2210/pdb6tlc/pdb
• 分子名称: Signal transducer and activator of transcription 3, Monobody (3 entities in total)
• 機能のキーワード: inhibitor, complex, stat3, monobody, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 156752.86

構造登録者

La Sala, G.,Lau, K.,Reynaud, A.,Pojer, F.,Hantschel, O. (登録日: 2019-12-02, 公開日: 2020-07-22, 最終更新日: 2024-01-24)

主引用文献

La Sala, G.,Michiels, C.,Kukenshoner, T.,Brandstoetter, T.,Maurer, B.,Koide, A.,Lau, K.,Pojer, F.,Koide, S.,Sexl, V.,Dumoutier, L.,Hantschel, O.
Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains.
Nat Commun, 11:4115-4115, 2020

PubMed Abstract: The transcription factor STAT3 is frequently activated in human solid and hematological malignancies and remains a challenging therapeutic target with no approved drugs to date. Here, we develop synthetic antibody mimetics, termed monobodies, to interfere with STAT3 signaling. These monobodies are highly selective for STAT3 and bind with nanomolar affinity to the N-terminal and coiled-coil domains. Interactome analysis detects no significant binding to other STATs or additional off-target proteins, confirming their exquisite specificity. Intracellular expression of monobodies fused to VHL, an E3 ubiquitin ligase substrate receptor, results in degradation of endogenous STAT3. The crystal structure of STAT3 in complex with monobody MS3-6 reveals bending of the coiled-coil domain, resulting in diminished DNA binding and nuclear translocation. MS3-6 expression strongly inhibits STAT3-dependent transcriptional activation and disrupts STAT3 interaction with the IL-22 receptor. Therefore, our study establishes innovative tools to interfere with STAT3 signaling by different molecular mechanisms.

PubMed: 32807795
DOI: 10.1038/s41467-020-17920-z

実験手法

X-RAY DIFFRACTION (2.9 Å)