Targeting the RT loop of Src SH3 in Platelets Prevents Thrombosis without Compromising Hemostasis.

ABSTRACT: Conventional antiplatelet agents indiscriminately inhibit both thrombosis and hemostasis, and the increased bleeding risk thus hampers their use at more aggressive dosages to achieve adequate effect. Blocking integrin αIIbβ3 outside-in signaling by separating the β3/Src interaction, yet to be proven in vivo, may nonetheless resolve this dilemma. Identification of a specific druggable target for this strategy remains a fundamental challenge as Src SH3 is known to be responsible for binding to not only integrin β3 but also the proteins containing the PXXP motif. In vitro and in vivo mutational analyses show that the residues, especially E97, in the RT loop of Src SH3 are critical for interacting with β3. DCDBS84, a small molecule resulting from structure-based virtual screening, is structura

SUBMITTER: Mao J 

PROVIDER: S-EPMC8895158 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature