Agonist Binding Domains of Glutamate Receptors: Structure and Function

The architecture of both families of glutamate-activated signaling proteins differs from that for other ligand-gated ion channels, on the one hand, and the majority of G-protein-coupled receptors, on the other. In both cases, a distinguishing feature of glutamate receptors is the structure that generates the agonist binding site. This domain shares homology with a large family of bacterial periplasmic binding proteins, a number of which have been crystallized. In these bacterial proteins, ligands bind in a cleft between two globular domains connected by beta strands. The binding of ligand stabilizes a closed cleft conformation in which the faces of each domain make contact with each other, while in the absence of ligand the domains assume an open clamshell-like conformation. In the case of glutamate receptors, which are thought to assemble as tetramers for the ion channel family and as dimers for the G-protein-coupled family, each subunit contains a complete copy of an agonist binding domain. Thus, there are four agonist binding sites per glutamate receptor ion channel and two agonist binding sites per G-protein receptor dimer. This understanding of the organization of the architecture of glutamate receptor channels emerged only recently and was brought into focus by the solution of crystal structures for the ligand binding domains of two ion channels and a G-protein-coupled glutamate receptor.