期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 24, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/ijms24109009
关键词
Hippo pathway; TEAD4/YAP1 interaction; chemical modification; Markov state model; free energy perturbation
The Hippo pathway is a conserved signaling network involved in cellular regulatory processes, and the overexpression of YAPs in the Hippo-off state is common in solid tumors. Inhibitors targeting the interaction sites between TEAD and YAP have been developed, and the palmitate-binding pocket in TEAD1-4 proteins is the most effective target. Through experimental screening and chemical modification, six new allosteric inhibitors were identified, and four of them showed enhanced communication between TEAD4 and YAP1 domains.
The Hippo pathway is an evolutionary conserved signaling network involved in several cellular regulatory processes. Dephosphorylation and overexpression of Yes-associated proteins (YAPs) in the Hippo-off state are common in several types of solid tumors. YAP overexpression results in its nuclear translocation and interaction with transcriptional enhanced associate domain 1-4 (TEAD1-4) transcription factors. Covalent and non-covalent inhibitors have been developed to target several interaction sites between TEAD and YAP. The most targeted and effective site for these developed inhibitors is the palmitate-binding pocket in the TEAD1-4 proteins. Screening of a DNA-encoded library against the TEAD central pocket was performed experimentally to identify six new allosteric inhibitors. Inspired by the structure of the TED-347 inhibitor, chemical modification was performed on the original inhibitors by replacing secondary methyl amide with a chloromethyl ketone moiety. Various computational tools, including molecular dynamics, free energy perturbation, and Markov state model analysis, were employed to study the effect of ligand binding on the protein conformational space. Four of the six modified ligands were associated with enhanced allosteric communication between the TEAD4 and YAP1 domains indicated by the relative free energy perturbation to original molecules. Phe229, Thr332, Ile374, and Ile395 residues were revealed to be essential for the effective binding of the inhibitors.
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