Arnaout and colleagues report the crystal structure of the extracellular segment of integrin V3 in complex with an RGD ligand.
Although integrins bind to a structurally diverse range of ligands, most of these ligands contain the sequence Arg–Gly–Asp (RGD). The structural basis for this cation-dependent interaction has been unclear, but now, in Science, Arnaout and colleagues report the crystal structure of the extracellular segment of integrin V3 in complex with an RGD ligand.
Integrins are composed of an alpha ()and beta ()subunit — both type I membrane proteins with large extracellular domains — and fall into two classes depending on the presence or absence of an A domain. Studies on the structure of A have previously shown that a metal-ion-dependent adhesion site (MIDAS) at the ligand-binding interface is required for ligand interactions with A-containing integrins. In V3, which lacks A, Arnaout and co-workers found that ligand binding is mediated by an A-like A domain in 3. Surprisingly, A acquires two cations on complex formation — one in MIDAS and another in a ligand-associated metal-binding site (LIMBS). They propose that LIMBS, which does not directly contact RGD, stabilizes the ligand-binding surface.
The authors found that RGD binds at the major interface between V and 3, and induces both tertiary and quaternary structural changes, which probably represent "a minimalist view" of the changes in integrins that are required for cell signalling. Although the ligand used here was synthetic, its RGD motif is almost conformationally identical to that present in a known natural ligand, which indicates that this structure can be used to understand integrin interactions with other RGD-containing ligands.
Rachel Smallridge
References
Xiong, J.-P. et al. Crystal structure of the extracellular segment of integrin V3 in complex with an Arg–Gly–Asp ligand. Science296, 151–155 (2002) | PubMed |
Plow, E. F. et al. Ligand binding to integrins. J. Biol. Chem.275, 21785–21788 (2000) | Article | PubMed |
V
3 in complex with an RGD ligand.
