The study investigates the structural basis for allosteric regulation in integrins and the binding of fibrinogen-mimetic therapeutics to platelet integrin α10β3. Crystal structures of αIIbβ3 fragments reveal the high-affinity, open conformation of the integrin headpiece, its interaction with therapeutic antagonists, and the allosteric movements linking the ligand binding site of the βI domain to α7-helix displacement and outward swing of the hybrid domain. Allostery in the β3 I domain alters three metal binding sites, associated loops, and α1- and α7-helices. The piston-like displacement of the α7-helix causes a 62° reorientation between the β3 I and hybrid domains, while transmission through the rigidly connected plexin/semaphorin/integrin (PSI) domain in the upper β3 leg results in a 70 Å separation between the knees of the α and β legs, disrupting the low-affinity bent integrin conformation and positioning the high-affinity headpiece far above the cell surface. The study also examines the binding sites for ligand-mimetic antagonists and fibrinogen at the α/β subunit interface, and the structural rearrangements between the closed and open conformations, which are consistent with the exposure of ligand-induced binding sites (LIBS) and activation epitopes. The findings provide insights into the mechanism of integrin activation and the design of therapeutic agents.The study investigates the structural basis for allosteric regulation in integrins and the binding of fibrinogen-mimetic therapeutics to platelet integrin α10β3. Crystal structures of αIIbβ3 fragments reveal the high-affinity, open conformation of the integrin headpiece, its interaction with therapeutic antagonists, and the allosteric movements linking the ligand binding site of the βI domain to α7-helix displacement and outward swing of the hybrid domain. Allostery in the β3 I domain alters three metal binding sites, associated loops, and α1- and α7-helices. The piston-like displacement of the α7-helix causes a 62° reorientation between the β3 I and hybrid domains, while transmission through the rigidly connected plexin/semaphorin/integrin (PSI) domain in the upper β3 leg results in a 70 Å separation between the knees of the α and β legs, disrupting the low-affinity bent integrin conformation and positioning the high-affinity headpiece far above the cell surface. The study also examines the binding sites for ligand-mimetic antagonists and fibrinogen at the α/β subunit interface, and the structural rearrangements between the closed and open conformations, which are consistent with the exposure of ligand-induced binding sites (LIBS) and activation epitopes. The findings provide insights into the mechanism of integrin activation and the design of therapeutic agents.