4RE1

Crystal structure of human TEAD1 and disulfide-engineered YAP

Summary for 4RE1

• Entry DOI: 10.2210/pdb4re1/pdb
• Descriptor: Transcriptional enhancer factor TEF-1, Yorkie homolog, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: immunoglobulin-like fold, transcription regulation, dna-binding, protein-protein interaction, phosphoprotein, nucleus, transcription-protein binding complex, transcription/protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P28347; Cytoplasm: P46937
• Total number of polymer chains: 4
• Total formula weight: 83009.26

Authors

Xu, Z.,Zhou, Z. (deposition date: 2014-09-21, release date: 2014-11-19, Last modification date: 2024-10-30)

Primary citation

Zhou, Z.,Hu, T.,Xu, Z.,Lin, Z.,Zhang, Z.,Feng, T.,Zhu, L.,Rong, Y.,Shen, H.,Luk, J.M.,Zhang, X.,Qin, N.
Targeting Hippo pathway by specific interruption of YAP-TEAD interaction using cyclic YAP-like peptides.
Faseb J., 29:724-732, 2015

PubMed Abstract: Hippo signaling pathway is emerging as a novel target for anticancer therapy because it plays key roles in organ size control and tumorigenesis. As the downstream effectors, Yes-associated protein (YAP)-transcriptional enhancer activation domain family member (TEAD) association is essential for YAP-driven oncogenic activity, while TEAD is largely dispensable for normal tissue growth. We present the design of YAP-like peptides (17mer) to occupy the interface 3 on TEAD. Introducing cysteines at YAP sites 87 and 96 can induce disulfide formation, as confirmed by crystallography. The engineered peptide significantly improves the potency in disrupting YAP-TEAD interaction in vitro. To confirm that blocking YAP-TEAD complex formation by directly targeting on TEAD is a valid approach, we report a significant reduction in tumor growth rate in a hepatocellular carcinoma xenograft model after introducing the dominant-negative mutation (Y406H) of TEAD1 to abolish YAP-TEAD interaction. Our results suggest that targeting TEAD is a promising strategy against YAP-induced oncogenesis.

PubMed: 25384421
DOI: 10.1096/fj.14-262980

Experimental method

X-RAY DIFFRACTION (2.2 Å)