6E5G

Crystal structure of human TEAD2-Yap binding domain covalently bound to an allosteric regulator

Summary for 6E5G

• Entry DOI: 10.2210/pdb6e5g/pdb
• Descriptor: Transcriptional enhancer factor TEF-4, 1-(2-{[3-(trifluoromethyl)phenyl]amino}phenyl)ethan-1-one (3 entities in total)
• Functional Keywords: inhibitor, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 53987.01

Authors

Bum-Erdene, K.,Gonzalez-Gutierrez, G.,Meroueh, S.O. (deposition date: 2018-07-20, release date: 2019-01-09, Last modification date: 2024-10-16)

Primary citation

Bum-Erdene, K.,Zhou, D.,Gonzalez-Gutierrez, G.,Ghozayel, M.K.,Si, Y.,Xu, D.,Shannon, H.E.,Bailey, B.J.,Corson, T.W.,Pollok, K.E.,Wells, C.D.,Meroueh, S.O.
Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction.
Cell Chem Biol, 26:378-, 2019

PubMed Abstract: The Hippo pathway coordinates extracellular signals onto the control of tissue homeostasis and organ size. Hippo signaling primarily regulates the ability of Yap1 to bind and co-activate TEA domain (TEAD) transcription factors. Yap1 tightly binds to TEAD4 via a large flat interface, making the development of small-molecule orthosteric inhibitors highly challenging. Here, we report small-molecule TEAD⋅Yap inhibitors that rapidly and selectively form a covalent bond with a conserved cysteine located within the unique deep hydrophobic palmitate-binding pocket of TEADs. Inhibition of TEAD4 binding to Yap1 by these compounds was irreversible and occurred on a longer time scale. In mammalian cells, the compounds formed a covalent complex with TEAD4, inhibited its binding to Yap1, blocked its transcriptional activity, and suppressed expression of connective tissue growth factor. The compounds inhibited cell viability of patient-derived glioblastoma spheroids, making them suitable as chemical probes to explore Hippo signaling in cancer.

PubMed: 30581134
DOI: 10.1016/j.chembiol.2018.11.010

Experimental method

X-RAY DIFFRACTION (2.43 Å)