Crystal Structure of the Extracellular Segment of Integrin αVβ3 in Complex with an Arg-Gly-Asp Ligand

TLDR

The structural basis for divalent cation–dependent binding of heterodimeric αβ integrins to Arg‑Gly‑Asp ligands, which triggers necessary tertiary and quaternary rearrangements for cell signaling, remains unknown. We determined the crystal structure of the extracellular segment of integrin αVβ3 bound to a cyclic Arg‑Gly‑Asp peptide, revealing ligand binding at the αV–β3 interface, extensive contacts, and ligand‑induced tertiary and quaternary rearrangements, including βA domain cation coordination and a slight shift in αV orientation.

Abstract

The structural basis for the divalent cation–dependent binding of heterodimeric αβ integrins to their ligands, which contain the prototypical Arg-Gly-Asp sequence, is unknown. Interaction with ligands triggers tertiary and quaternary structural rearrangements in integrins that are needed for cell signaling. Here we report the crystal structure of the extracellular segment of integrin αVβ3 in complex with a cyclic peptide presenting the Arg-Gly-Asp sequence. The ligand binds at the major interface between the αV and β3 subunits and makes extensive contacts with both. Both tertiary and quaternary changes are observed in the presence of ligand. The tertiary rearrangements take place in βA, the ligand-binding domain of β3; in the complex, βA acquires two cations, one of which contacts the ligand Asp directly and the other stabilizes the ligand-binding surface. Ligand binding induces small changes in the orientation of αV relative to β3.