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Evolution of glutamate interactions during binding to a glutamate receptor

Nature Chemical Biology volume 1, pages 329–332 (2005)Cite this article

Abstract

Glutamate receptors are the predominant mediators of excitatory synaptic signals in the central nervous system and are important in learning and memory as well as in diverse neuropathologies including epilepsy and ischemia1,2,3,4,5. Their primary function is to receive the chemical signal glutamate (1), which binds to an extracellular domain in the receptor, and convert it into an electrical signal through the formation of cation-permeable transmembrane channels6,7,8,9. Recently described end-state apo and ligated structures of the ligand-binding domain of a rat glutamate receptor provide a first view of specific molecular interactions between the ligand and the receptor that are central to the allosteric regulation of function in this protein7,10,11,12,13,14,15. Yet there is little information on the mechanism and the structures of intermediates (if any) formed during the ligand-binding process16. Here we have used time-resolved vibrational spectroscopy to show that the process involves a sequence of interleaved ligand and protein changes that starts with the docking of glutamate at the α-carboxylate moiety and ends with the establishment of the interactions between the γ-carboxylate of glutamate and the protein.

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Figure 1: Time-resolved FTIR difference spectra showing the evolution of the glutamate and protein vibrational modes during agonist binding to the GluR2S1S2-E705D.
Figure 2: The time dependence for the changes in the intensities of the vibrational modes during the agonist binding process.
Figure 3: Difference FTIR spectrum between glutamate and apo state of GluR2S1S2-Y450F and difference FTIR spectrum between glutamate and apo state of wild type (WT) GluR2S1S2.
Figure 4: Mechanism of ligand binding in the glutamate ligand-binding domain.

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Acknowledgements

This work was supported by the National Science Foundation (MCB-0444352), the National Institutes of Health (1R03AA015682-01) and the American Heart Foundation, Texas Affiliate.

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Authors and Affiliations

  1. Department of Integrative Biology and Pharmacology, 6431 Fannin, University of Texas Health Science Center, Houston, 77030, Texas, USA

    Qing Cheng, Mei Du, Gomathi Ramanoudjame & Vasanthi Jayaraman

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Correspondence to Vasanthi Jayaraman.

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Supplementary information

Supplementary Fig. 1

Time-resolved FTIR difference spectra showing the evolution of the glutamate and protein vibrational modes during agonist binding to the GluR2S1S2. (PDF 19 kb)

Supplementary Fig. 2

Difference FTIR spectrum between glutamate-bound and unligated form of GluR2 S1S2-E705D protein in D2O, and glutamate-bound and unligated form of GluR2 S1S2-E705D protein in H2O. (PDF 11 kb)

Supplementary Fig. 3

Difference FTIR spectrum between glutamate and D2O buffer, glutamate and H2O buffer, [γ-13C]glutamate and H2O buffer and [α-13C]glutamate and H2O buffer (PDF 23 kb)

Supplementary Methods (PDF 129 kb)

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Cheng, Q., Du, M., Ramanoudjame, G. et al. Evolution of glutamate interactions during binding to a glutamate receptor. Nat Chem Biol 1, 329–332 (2005). https://doi.org/10.1038/nchembio738

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