STRUCTURE OF A GLUTAMATE-RECEPTOR LIGAND-BINDING CORE IN COMPLEX WITHKAINATE

Ionotropic glutamate receptors (iGluRs) mediate excitatory synaptic tr ansmission in vertebrates and invertebrates through ligand-induced ope ning of transmembrane ion channels. iGluRs are segregated into three s ubtypes according to their sensitivity to the agonists AMPA (alpha-ami no-3-hydroxy-5-methyl-4-isoxazole propionic acid), kainate (a structur al analogue of glutamate) or NMDA (N-methyl-D-aspartate) (Fig.1). iGlu Rs are important in the development and function of the nervous system , are essential in memory and learning, and are either implicated in o r have causal roles in dysfunctions ranging from Alzheimer's, Parkinso n's and Huntington's diseases, schizophrenia, epilepsy and Rasmussen's encephalitis to stroke(1,2). Development of iGluR agonists and antago nists has been hampered by a lack of high-resolution structural inform ation. Here we describe the crystal structure of an iGluR ligand-bindi ng region in a complex with the neurotoxin (agonist) kainate. The bilo bed structure shows the determinants of receptor-agonist interactions and how ligand-binding specificity and affinity are altered by remote residues and the redox state of the conserved disulphide bond, The str ucture indicates mechanisms for allosteric effector action and for lig and-induced channel gating. The information provided by this structure will be essential in designing new ligands.