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The ligand binding function of integrins can be modulated by various monoclonal antibodies by both direct and indirect mechanisms. We have characterized an anti-β1 antibody, SG/19, that had been reported to inhibit the function of the β1 integrin on the cell surface. SG/19 recognized the wild type β1 subunit that exists in a conformational equilibrium between the high and low affinity states but bound poorly to a mutant β1 integrin that had been locked in a high affinity state. Epitope mapping of SG/19 revealed that Thr82 in the β1 subunit, located at the outer face of the boundary between the I-like and hybrid domains, was the key binding determinant for this antibody. Direct visualization of the α5β1 headpiece fragment in complex with SG/19 Fab with electron microscopy confirmed the location of the binding surface and showed that the ligand binding site is not occluded by the bound Fab. Surface plasmon resonance showed that α5β1 integrin bound by SG/19 maintained a low affinity toward its physiological ligand fibronectin (Fn) whereas binding by function-blocking anti-α5 antibodies resulted in a complete loss of fibronectin binding. Thus a class of the anti-β antibodies represented by SG/19 attenuate the ligand binding function by restricting the conformational shift to the high affinity state involving the swing-out of the hybrid domain without directly interfering with ligand docking.

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Journal of Biological Chemistry

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