5DQE

Crystal structure of human transcription factor TEAD2 in complex with bromo-fenamic acid

5DQE の概要

• エントリーDOI: 10.2210/pdb5dqe/pdb
• 関連するPDBエントリー: 3L15 5DQ8
• 分子名称: Transcriptional enhancer factor TEF-4, 2-[(3-bromophenyl)amino]benzoic acid (3 entities in total)
• 機能のキーワード: flufenamates, hippo pathway, cancer therapy, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55854.58

構造登録者

Han, X.,Luo, X. (登録日: 2015-09-14, 公開日: 2015-11-25, 最終更新日: 2023-09-27)

主引用文献

Pobbati, A.V.,Han, X.,Hung, A.W.,Weiguang, S.,Huda, N.,Chen, G.Y.,Kang, C.,Chia, C.S.,Luo, X.,Hong, W.,Poulsen, A.
Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy.
Structure, 23:2076-2086, 2015

PubMed Abstract: The human TEAD family of transcription factors (TEAD1-4) is required for YAP-mediated transcription in the Hippo pathway. Hyperactivation of TEAD's co-activator YAP contributes to tissue overgrowth and human cancers, suggesting that pharmacological interference of TEAD-YAP activity may be an effective strategy for anticancer therapy. Here we report the discovery of a central pocket in the YAP-binding domain (YBD) of TEAD that is targetable by small-molecule inhibitors. Our X-ray crystallography studies reveal that flufenamic acid, a non-steroidal anti-inflammatory drug (NSAID), binds to the central pocket of TEAD2 YBD. Our biochemical and functional analyses further demonstrate that binding of NSAIDs to TEAD inhibits TEAD-YAP-dependent transcription, cell migration, and proliferation, indicating that the central pocket is important for TEAD function. Therefore, our studies discover a novel way of targeting TEAD transcription factors and set the stage for therapeutic development of specific TEAD-YAP inhibitors against human cancers.

PubMed: 26592798
DOI: 10.1016/j.str.2015.09.009

実験手法

X-RAY DIFFRACTION (2.183 Å)