7v1a

Publication Abstract from PubMed

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.

Inhibition of talin-induced integrin activation by a double-hit stapled peptide.,Gao T, Cho EA, Zhang P, Wu J Structure. 2023 Aug 3;31(8):948-957.e3. doi: 10.1016/j.str.2023.05.016. Epub 2023 , Jun 26. PMID:37369205^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.