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Structure of a glutamate-receptor ligand-binding core in complex with kainate

Abstract

Ionotropic glutamate receptors (iGluRs) mediate excitatory synaptic transmission in vertebrates and invertebrates through ligand-induced opening of transmembrane ion channels. iGluRs are segregated into three subtypes according to their sensitivity to the agonists AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), kainate (a structural analogue of glutamate) or NMDA (N-methyl-D-aspartate) (Fig. 1). iGluRs are important in the development and function of the nervous system, are essential in memory and learning, and are either implicated in or have causal roles in dysfunctions ranging from Alzheimer's, Parkinson's and Huntington's diseases, schizophrenia, epilepsy and Rasmussen's encephalitis to stroke1,2. Development of iGluR agonists and antagonists has been hampered by a lack of high-resolution structural information. Here we describe the crystal structure of an iGluR ligand-binding region in a complex with the neurotoxin (agonist) kainate. The bilobed 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 structure indicates mechanisms for allosteric effector action and for ligand-induced channel gating. The information provided by this structure will be essential in designing new ligands.

The numbering of substituents on the pyrrolidine ring of kainate is as follows: nitrogen, 1; carboxylate, 2; carboxyl methyl, 3; and isopropenyl, 4.

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Figure 2: Structure of the complex of GluR2 S1S2 and kainate.
Figure 3: Superposition of the complex of GluR2 S1S2 and kainate (KA) with the closed form of QBP10.
Figure 4: Sequence identity between iGluRs.

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Acknowledgements

We thank C. Lima and other members of the Hendrickson laboratory for assistance; J. Lidestri for maintenance of the X-ray laboratory at Columbia University; A. Karlin, J. Javitch and M.Akabas for advice; S. Heinemann and M. Hartley for glutamate-receptor clones; C. Ogata for help with MAD data collection at NSLS X4a; T. Terwilliger for advice on the use of Solve; and W. Minor and Z.Otwinoski for a new version of the HKL suite of programs. Extra MAD data were collected at the Cornell High Energy Synchrotron Source (CHESS), which is supported by the NSF, using the Macromolecular Diffraction at CHESS (MacCHESS) facility, which is supported by an award from the NIH. N.A. was supported by an NIH Ophthalmology training grant. E.G. is an NSF Young Investigator and the recipient of an Alfred P. Sloan Research Fellowship.

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Armstrong, N., Sun, Y., Chen, GQ. et al. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395, 913–917 (1998). https://doi.org/10.1038/27692

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