Abstract 7384: Regulation of phosphorylated VGLL1 by the positively charged binding pocket on the surface of TEAD4

Abstract Vestigial-like 1 (VGLL1) is a transcriptional co-activator that binds to TEA domain-containing transcription factors (TEADs), regulating hippo pathway. High expression of VGLL1 is associated with gastric cancer, breast cancer, and pancreatic cancers. VGLL1 is transcriptionally regulated by PI3K/β-catenin signaling and is phosphorylated by ribosomal S6 kinase 2 (RSK2) in the presence of TGF-β. It is clear that phosphorylation at S84 of the VGLL1 protein is critical for its interaction with TEAD4 to express their target genes involved in the proliferation and metastasis of cancer cells. In the isothermal titration calorimetry study, we observed S84-phosphorylated VGLL1 peptide bound to TEAD4. However, it is difficult to understand structure-based molecular mechanism of the phosphorylated VGLL1 at S84 due to lack of the detailed human VGLL1-TEAD4 complex structure for rational drug design. In this study, we modeled full-length human VGLL1-TEAD4 or YAP1-TEAD4 complexes and performed MMPBSA calculations or Kd/Ki predictions followed by MD simulations using Pharmaco-Net's CNN-based artificial intelligence model. Our study suggests that a positively charged binding pocket on the surface of TEAD4 can regulate interaction between Trp243 from YAP1 and phosphorylated-Ser84 from VGLL1. The newly identified binding pocket is composed of Lys297, Val414, and Tyr429, which can interact with phosphorylated Ser84 residue and maintain Omega loop-like structure shown in YAP1-TEAD4 complex. The computed binding energy for phosphorylated-VGLL1-TEAD was -134.80 +/- 8.20 Kcal/mol which was a similar binding energy to YAP1-TEAD4 complex. In addition, global peptide docking using S84-containing-VGLL1 peptide (SCVP) indicated that SCVP can bind to the same binding pocket with average 1.39 μM. This suggested that there could be a novel therapeutic approach targeting this interaction with SCVP, an agent that seems to mimic phosphor-VGLL1 interaction and thus demonstrates promise as a potential therapeutic intervention. Nevertheless, further experimental verification and clinical investigations are needed to validate these innovative findings. Citation Format: Jae Mun Choi, Huong Van Le, Young Bin Park, Yu Kyung Yun, Jun Hong Kim, Jonathan Wilianto, Nuzup Shadiev, Chul Sung, Bonsu Ku, Kwan-Young Chang, Misun Won. Regulation of phosphorylated VGLL1 by the positively charged binding pocket on the surface of TEAD4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7384.