8C17

Crystal structure of TEAD4 in complex with peptide 1

Summary for 8C17

• Entry DOI: 10.2210/pdb8c17/pdb
• Descriptor: Transcriptional enhancer factor TEF-3, Stapled peptide, GLYCEROL, ... (5 entities in total)
• Functional Keywords: complex, inhibitor, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 28260.91

Authors

Scheufler, C.,Kallen, J. (deposition date: 2022-12-20, release date: 2023-03-15, Last modification date: 2024-05-29)

Primary citation

Mesrouze, Y.,Gubler, H.,Villard, F.,Boesch, R.,Ottl, J.,Kallen, J.,Reid, P.C.,Scheufler, C.,Marzinzik, A.L.,Chene, P.
Biochemical and Structural Characterization of a Peptidic Inhibitor of the YAP:TEAD Interaction That Binds to the alpha-Helix Pocket on TEAD.
Acs Chem.Biol., 18:643-651, 2023

PubMed Abstract: The TEAD transcription factors are the most distal elements of the Hippo pathway, and their transcriptional activity is regulated by several proteins, including YAP. In some cancers, the Hippo pathway is deregulated and inhibitors of the YAP:TEAD interaction are foreseen as new anticancer drugs. The binding of YAP to TEAD is driven by the interaction of an α-helix and an Ω-loop present in its TEAD-binding domain with two distinct pockets at the TEAD surface. Using the mRNA-based display technique to screen a library of -translated cyclic peptides, we identified a peptide that binds with a nanomolar affinity to TEAD. The X-ray structure of this peptide in complex with TEAD reveals that it interacts with the α-helix pocket. Under our experimental conditions, this peptide can form a ternary complex with TEAD and YAP. Furthermore, combining it with a peptide binding to the Ω-loop pocket gives an additive inhibitory effect on the YAP:TEAD interaction. Overall, our results show that it is possible to identify nanomolar inhibitors of the YAP:TEAD interaction that bind to the α-helix pocket, suggesting that developing such compounds might be a strategy to treat cancers where the Hippo pathway is deregulated.

PubMed: 36825662
DOI: 10.1021/acschembio.2c00936

Experimental method

X-RAY DIFFRACTION (2.25 Å)