6CDY

Crystal structure of TEAD complexed with its inhibitor

Summary for 6CDY

• Entry DOI: 10.2210/pdb6cdy/pdb
• Descriptor: Transcriptional enhancer factor TEF-4, 2-[(4H-1,2,4-triazol-3-yl)sulfanyl]-N-{4-[(3s,5s,7s)-tricyclo[3.3.1.1~3,7~]decan-1-yl]phenyl}acetamide (3 entities in total)
• Functional Keywords: transcription factor, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 55715.18

Authors

LIU, S.,HAN, X.,LUO, X. (deposition date: 2018-02-09, release date: 2020-07-01, Last modification date: 2023-10-04)

Primary citation

Li, Q.,Sun, Y.,Jarugumilli, G.K.,Liu, S.,Dang, K.,Cotton, J.L.,Xiol, J.,Chan, P.Y.,DeRan, M.,Ma, L.,Li, R.,Zhu, L.J.,Li, J.H.,Leiter, A.B.,Ip, Y.T.,Camargo, F.D.,Luo, X.,Johnson, R.L.,Wu, X.,Mao, J.
Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription.
Cell Stem Cell, 26:675-692.e8, 2020

PubMed Abstract: Intestinal homeostasis is tightly regulated by complex yet poorly understood signaling networks. Here, we demonstrate that Lats1/2, the core Hippo kinases, are essential to maintain Wnt pathway activity and intestinal stem cells. Lats1/2 deletion leads to loss of intestinal stem cells but drives Wnt-uncoupled crypt expansion. To explore the function of downstream transcriptional enhanced associate domain (TEAD) transcription factors, we identified a selective small-molecule reversible inhibitor of TEAD auto-palmitoylation that directly occupies its lipid-binding site and inhibits TEAD-mediated transcription in vivo. Combining this chemical tool with genetic and proteomics approaches, we show that intestinal Wnt inhibition by Lats deletion is Yes-associated protein (YAP)/transcriptional activator with PDZ-binding domain (TAZ) dependent but TEAD independent. Mechanistically, nuclear YAP/TAZ interact with Groucho/Transducin-Like Enhancer of Split (TLE) to block Wnt/T-cell factor (TCF)-mediated transcription, and dual inhibition of TEAD and Lats suppresses Wnt-uncoupled Myc upregulation and epithelial over-proliferation in Adenomatous polyposis coli (APC)-mutated intestine. Our studies highlight a pharmacological approach to inhibit TEAD palmitoylation and have important implications for targeting Wnt and Hippo signaling in human malignancies.

PubMed: 32259481
DOI: 10.1016/j.stem.2020.03.002

Experimental method

X-RAY DIFFRACTION (2.32 Å)