6UYC

Crystal structure of TEAD2 bound to Compound 2

6UYC の概要

• エントリーDOI: 10.2210/pdb6uyc/pdb
• 分子名称: 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)
• 機能のキーワード: tead, yap binding domain, transcription inhibitor, palmitoylation inhibitor, transcription-inhibitor complex, transcription/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 54221.20

構造登録者

Noland, C.L.,Holden, J.K.,Crawford, J.J.,Zbieg, J.R.,Cunningham, C.N. (登録日: 2019-11-12, 公開日: 2020-06-24, 最終更新日: 2023-10-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.658 Å)