6sba
Crystal Structure of mTEAD with a VGL4 Tertiary Structure Mimetic
Structural highlights
FunctionTEAD4_MOUSE 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 (By similarity). Might play a role in the embryonic development of skeletal muscle. Publication Abstract from PubMedTranscription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein-protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators. A protein tertiary structure mimetic modulator of the Hippo signalling pathway.,Adihou H, Gopalakrishnan R, Forster T, Gueret SM, Gasper R, Geschwindner S, Carrillo Garcia C, Karatas H, Pobbati AV, Vazquez-Chantada M, Davey P, Wassvik CM, Pang JKS, Soh BS, Hong W, Chiarparin E, Schade D, Plowright AT, Valeur E, Lemurell M, Grossmann TN, Waldmann H Nat Commun. 2020 Oct 27;11(1):5425. doi: 10.1038/s41467-020-19224-8. PMID:33110077[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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