The methods and compositions described herein are based, in part, on the discovery that the introduction of a disulfide bond into an integrin polypeptide by the substitution of at least one cysteine residue in the polypeptide permits stabilization of the integrin in a “closed/inactive” state. This stabilizing disulfide bond permits integrins to be screened for a candidate molecule that can bind to the closed state. In particular, this approach can be used to screen for agents that bind to the closed state of an integrin polypeptide, and are useful as therapeutic treatments to prevent integrin activation.