7V1A

Stapled TBS peptide from RIAM bound to talin R7R8 domains

Summary for 7V1A

• Entry DOI: 10.2210/pdb7v1a/pdb
• Descriptor: Talin-1, ASP-ILE-ASP-GLN-MET-PHE-SER-THR-LEU-LEU-GLY-GLU-MK8-ASP-LEU-LEU-MK8-GLN-SER, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: riam, talin, integrin, mrl, stapled, helix, cell adhesion
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 2
• Total formula weight: 33845.17

Authors

Zhang, P.,Gao, T.,Wu, J. (deposition date: 2022-05-11, release date: 2023-06-14, Last modification date: 2024-10-16)

Primary citation

Gao, T.,Cho, E.A.,Zhang, P.,Wu, J.
Inhibition of talin-induced integrin activation by a double-hit stapled peptide.
Structure, 31:948-, 2023

PubMed Abstract: Integrins are ubiquitously expressed cell-adhesion proteins. Activation of integrins is triggered by talin through an inside-out signaling pathway, which can be driven by RAP1-interacting adaptor molecule (RIAM) through its interaction with talin at two distinct sites. A helical talin-binding segment (TBS) in RIAM interacts with both sites in talin, leading to integrin activation. The bispecificity inspires a "double-hit" strategy for inhibiting talin-induced integrin activation. We designed an experimental peptidomimetic inhibitor, S-TBS, derived from TBS and containing a molecular staple, which leads to stronger binding to talin and inhibition of talin:integrin interaction. The crystallographic study validates that S-TBS binds to the talin rod through the same interface as TBS. Moreover, the helical S-TBS exhibits excellent cell permeability and effectively suppresses integrin activation in cells in a talin-dependent manner. Our results shed light on a new class of integrin inhibitors and a novel approach to design multi-specific peptidomimetic inhibitors.

PubMed: 37369205
DOI: 10.1016/j.str.2023.05.016

Experimental method

X-RAY DIFFRACTION (1.845 Å)