Computational design and experimental confirmation of a disulfide-stapled YAP helixα1-trap derived from TEAD4 helical hairpin to selectively capture YAP α1-helix with potent antitumor activity

Li, Kaipeng; Liu, Lijun

doi:10.1007/s10822-024-00572-2

J Comput Aided Mol Des

2024

DOI: 10.1007/s10822-024-00572-2

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Computational design and experimental confirmation of a disulfide-stapled YAP helixα1-trap derived from TEAD4 helical hairpin to selectively capture YAP α1-helix with potent antitumor activity

Kaipeng Li,

Lijun Liu

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TAZ‐hTrap: A Rationally Designed, Disulfide‐Stapled Tead Helical Hairpin Trap to Selectively Capture Hippo Signaling Taz With Potent Antigynecological Tumor Activity

Tang,

Du,

Wang

2024

J of Molecular Recognition

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Transcriptional enhanced associate domain (Tead)–mediated Hippo signaling pathway regulates diverse physiological processes; its dysfunction has been implicated in an increasing number of human gynecological cancers. The transcriptional coactivator with PDZ‐binding motif (Taz) binds to and then activates Tead through forming a three‐helix bundle (THB) at their complex interface. The THB is defined by a double‐helical hairpin from Tead and a single α‐helix from Taz, serving as the key interaction hotspot between Tead and Taz. In the present study, the helical hairpin was derived from Tead protein to generate a hairpin segment, which is a 25‐mer polypeptide consisting of a longer helical arm‐1 and a shorter helical arm‐2 as well as a flexible loop linker between them. Dynamics simulation and energetics characterization revealed that the hairpin peptide is intrinsically disordered when splitting from its protein context, thus incurring a large entropy penalty upon binding to Taz α‐helix. A disulfide bridge was introduced across the two helical arms of hairpin peptide to obtain a strong binder termed TAZ‐hTrap, which can maintain in a considerably structured, native‐like conformation in unbound state, and the entropy penalty was minimized by disulfide stapling to effectively improve its affinity toward the α‐helix. These computational findings can be further substantiated by circular dichroism and fluorescence polarization at molecular level, and viability assay also observed a potent cytotoxic effect on diverse human gynecological tumors at cellular level. In addition, we further demonstrated that the TAZ‐hTrap has a good selectivity for its cognate Taz over other noncognate proteins that share a high conservation with the Taz α‐helix.

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TAZ‐hTrap: A Rationally Designed, Disulfide‐Stapled Tead Helical Hairpin Trap to Selectively Capture Hippo Signaling Taz With Potent Antigynecological Tumor Activity

Tang,

Du,

Wang

2024

J of Molecular Recognition

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Computational design and experimental confirmation of a disulfide-stapled YAP helixα1-trap derived from TEAD4 helical hairpin to selectively capture YAP α1-helix with potent antitumor activity

Cited by 1 publication

References 48 publications

TAZ‐hTrap: A Rationally Designed, Disulfide‐Stapled Tead Helical Hairpin Trap to Selectively Capture Hippo Signaling Taz With Potent Antigynecological Tumor Activity

TAZ‐hTrap: A Rationally Designed, Disulfide‐Stapled Tead Helical Hairpin Trap to Selectively Capture Hippo Signaling Taz With Potent Antigynecological Tumor Activity

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