8c17
From Proteopedia
Crystal structure of TEAD4 in complex with peptide 1
Structural highlights
FunctionTEAD4_HUMAN Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and non-cooperatively to the Sph and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription. Binds to the M-CAT motif.[1] [2] Publication Abstract from PubMedThe TEAD transcription factors are the most distal elements of the Hippo pathway, and their transcriptional activity is regulated by several proteins, including YAP. In some cancers, the Hippo pathway is deregulated and inhibitors of the YAP:TEAD interaction are foreseen as new anticancer drugs. The binding of YAP to TEAD is driven by the interaction of an alpha-helix and an Omega-loop present in its TEAD-binding domain with two distinct pockets at the TEAD surface. Using the mRNA-based display technique to screen a library of in vitro-translated cyclic peptides, we identified a peptide that binds with a nanomolar affinity to TEAD. The X-ray structure of this peptide in complex with TEAD reveals that it interacts with the alpha-helix pocket. Under our experimental conditions, this peptide can form a ternary complex with TEAD and YAP. Furthermore, combining it with a peptide binding to the Omega-loop pocket gives an additive inhibitory effect on the YAP:TEAD interaction. Overall, our results show that it is possible to identify nanomolar inhibitors of the YAP:TEAD interaction that bind to the alpha-helix pocket, suggesting that developing such compounds might be a strategy to treat cancers where the Hippo pathway is deregulated. Biochemical and Structural Characterization of a Peptidic Inhibitor of the YAP:TEAD Interaction That Binds to the alpha-Helix Pocket on TEAD.,Mesrouze Y, Gubler H, Villard F, Boesch R, Ottl J, Kallen J, Reid PC, Scheufler C, Marzinzik AL, Chene P ACS Chem Biol. 2023 Mar 17;18(3):643-651. doi: 10.1021/acschembio.2c00936. Epub , 2023 Feb 24. PMID:36825662[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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