Ajaybabu V. Pobbati1,1,5,*, Xiao Han2,4,5, Alvin W. Hung4,5, Seetoh Weiguang4, Nur Huda4, Guo-Ying Chen4, CongBao Kang4, Cheng San Brian4, Xuelian Luo3,**, Wanjin Hong1 and Anders Poulsen 4,***
1 Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Singapore 138673
2 Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China, 130012
3 Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA
4 Experimental Therapeutics Centre, A*STAR, 31 Biopolis Way, #3-01, Singapore 138669
5 Co-first author
* Correspondence: email@example.com
** Correspondence: firstname.lastname@example.org
*** Correspondence: email@example.com
Published online in Structure on 22 October 2015.
The human TEAD family of transcription factors (TEAD1-4) is required for YAP-mediated transcription in the Hippo pathway. Hyperactivation of TEAD’s co-activator YAP contributes to tissue overgrowth and human cancers, suggesting that pharmacological interference of TEAD-YAP activity may be an effective strategy for anticancer therapy. Here we report the discovery of a central pocket in the YAP-binding domain (YBD) of TEAD that is targetable by small molecule inhibitors. Our X-ray crystallography studies reveal that flufenamic acid, a non-steroidal anti-inflammatory drug (NSAID), binds to the central pocket of TEAD2 YBD. Our biochemical and functional analyses further demonstrate that binding of NSAIDs to TEAD inhibits TEAD-YAP-dependent transcription, cell migration and proliferation, indicating that the central pocket is important for TEAD function. Therefore, our studies discover a novel way of targeting TEAD transcription factors and set the stage for therapeutic development of specific TEAD-YAP inhibitors against human cancers.
Structure of the TEAD2-flufenamic acid Complex
(A) Crystal structure of the TEAD2-FA complex reveals that FA binds to the central pocket in TEAD. TEAD2 YBD is colored green. FA is shown as pink sticks.
(B) A cross-section of the surface drawing of TEAD2 YBD shows FA occupying the central pocket.
(C) Simulated annealing omit map contoured at 1 s for FA.
(D) Detailed view of the TEAD-FA interaction. FA and FA-contacting residues in the central pocket are shown as pink and grey sticks, respectively. The hydrogen bond between FA and C380 is shown as a green dash line.
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