8CUH

Crystal structure of human TEAD2 complexed with its inhibitor TM2.

Summary for 8CUH

• Entry DOI: 10.2210/pdb8cuh/pdb
• Descriptor: Transcriptional enhancer factor TEF-4, 4-[3-(2-cyclohexylethoxy)benzoyl]-N-phenylpiperazine-1-carboxamide (3 entities in total)
• Functional Keywords: transcription factor, transcription-transcription inhibitor complex, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 55849.31

Authors

Liu, S.,Luo, X. (deposition date: 2022-05-17, release date: 2022-11-23, Last modification date: 2023-10-25)

Primary citation

Hu, L.,Sun, Y.,Liu, S.,Erb, H.,Singh, A.,Mao, J.,Luo, X.,Wu, X.
Discovery of a new class of reversible TEA-domain transcription factor inhibitors with a novel binding mode.
Elife, 11:-, 2022

PubMed Abstract: The TEA domain (TEAD) transcription factor forms a transcription co-activation complex with the key downstream effector of the Hippo pathway, YAP/TAZ. TEAD-YAP controls the expression of Hippo-responsive genes involved in cell proliferation, development, and tumorigenesis. Hyperactivation of TEAD-YAP activities is observed in many human cancers and is associated with cancer cell proliferation, survival, and immune evasion. Therefore, targeting the TEAD-YAP complex has emerged as an attractive therapeutic approach. We previously reported that the mammalian TEAD transcription factors (TEAD1-4) possess auto-palmitoylation activities and contain an evolutionarily conserved palmitate-binding pocket (PBP), which allows small-molecule modulation. Since then, several reversible and irreversible inhibitors have been reported by binding to PBP. Here, we report a new class of TEAD inhibitors with a novel binding mode. Representative analog TM2 shows potent inhibition of TEAD auto-palmitoylation both in vitro and in cells. Surprisingly, the co-crystal structure of the human TEAD2 YAP-binding domain (YBD) in complex with TM2 reveals that TM2 adopts an unexpected binding mode by occupying not only the hydrophobic PBP, but also a new side binding pocket formed by hydrophilic residues. RNA-seq analysis shows that TM2 potently and specifically suppresses TEAD-YAP transcriptional activities. Consistently, TM2 exhibits strong antiproliferation effects as a single agent or in combination with a MEK inhibitor in YAP-dependent cancer cells. These findings establish TM2 as a promising small-molecule inhibitor against TEAD-YAP activities and provide new insights for designing novel TEAD inhibitors with enhanced selectivity and potency.

PubMed: 36398861
DOI: 10.7554/eLife.80210

Experimental method

X-RAY DIFFRACTION (2.4 Å)