6UYC

Crystal structure of TEAD2 bound to Compound 2

Summary for 6UYC

• Entry DOI: 10.2210/pdb6uyc/pdb
• Descriptor: Transcriptional enhancer factor TEF-4, N-{5-[(E)-2-(4,4-difluorocyclohexyl)ethenyl]-6-methoxypyridin-3-yl}methanesulfonamide, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (4 entities in total)
• Functional Keywords: tead, yap binding domain, transcription inhibitor, palmitoylation inhibitor, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 54221.20

Authors

Noland, C.L.,Holden, J.K.,Crawford, J.J.,Zbieg, J.R.,Cunningham, C.N. (deposition date: 2019-11-12, release date: 2020-06-24, Last modification date: 2023-10-11)

Primary citation

Holden, J.K.,Crawford, J.J.,Noland, C.L.,Schmidt, S.,Zbieg, J.R.,Lacap, J.A.,Zang, R.,Miller, G.M.,Zhang, Y.,Beroza, P.,Reja, R.,Lee, W.,Tom, J.Y.K.,Fong, R.,Steffek, M.,Clausen, S.,Hagenbeek, T.J.,Hu, T.,Zhou, Z.,Shen, H.C.,Cunningham, C.N.
Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling.
Cell Rep, 31:107809-107809, 2020

PubMed Abstract: The transcriptional enhanced associate domain (TEAD) family of transcription factors serves as the receptors for the downstream effectors of the Hippo pathway, YAP and TAZ, to upregulate the expression of multiple genes involved in cellular proliferation and survival. Recent work identified TEAD S-palmitoylation as critical for protein stability and activity as the lipid tail extends into a hydrophobic core of the protein. Here, we report the identification and characterization of a potent small molecule that binds the TEAD lipid pocket (LP) and disrupts TEAD S-palmitoylation. Using a variety of biochemical, structural, and cellular methods, we uncover that TEAD S-palmitoylation functions as a TEAD homeostatic protein level checkpoint and that dysregulation of this lipidation affects TEAD transcriptional activity in a dominant-negative manner. Furthermore, we demonstrate that targeting the TEAD LP is a promising therapeutic strategy for modulating the Hippo pathway, showing tumor stasis in a mouse xenograft model.

PubMed: 32579935
DOI: 10.1016/j.celrep.2020.107809

Experimental method

X-RAY DIFFRACTION (1.658 Å)