5DQE

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

Summary for 5DQE

• Entry DOI: 10.2210/pdb5dqe/pdb
• Related: 3L15 5DQ8
• Descriptor: Transcriptional enhancer factor TEF-4, 2-[(3-bromophenyl)amino]benzoic acid (3 entities in total)
• Functional Keywords: flufenamates, hippo pathway, cancer therapy, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 55854.58

Authors

Han, X.,Luo, X. (deposition date: 2015-09-14, release date: 2015-11-25, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.183 Å)