Stabilized low affinity conformation of integrins for drug discovery

Abstract

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.

1 . A method for identifying a candidate modulator of integrin activity, the method comprising (a) contacting an integrin polypeptide with a candidate agent, wherein the integrin polypeptide is locked into a desired conformation; and (b) detecting binding of the candidate agent to the integrin polypeptide, wherein binding of the candidate agent to the integrin polypeptide is indicative that the candidate agent is a candidate modulator of integrin activity.