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Glutamate receptor desensitization is mediated by changes in quaternary structure of the ligand binding domain.

Publication ,  Journal Article
Schauder, DM; Kuybeda, O; Zhang, J; Klymko, K; Bartesaghi, A; Borgnia, MJ; Mayer, ML; Subramaniam, S
Published in: Proc Natl Acad Sci U S A
April 9, 2013

Glutamate receptor ion channels are membrane proteins that mediate excitatory synaptic transmission in the central nervous system of vertebrates. Insight into molecular mechanisms underlying glutamate receptor gating is limited by lack of structural information for receptors trapped in different conformational states. Here, we report the use of single-particle cryoelectron tomography to determine the structures, at ∼21 Å resolution, of full-length GluK2 kainate receptors trapped in antagonist-bound resting and agonist-bound desensitized states. The resting state, stabilized by the competitive antagonist LY466195, closely resembles the crystal structure of the AMPA receptor GluA2, with well-resolved proximal and distal subunits exhibiting cross-over between the twofold symmetric amino terminal domain and a twofold symmetric ligand binding domain (LBD) dimer of dimers assembly. In the desensitized state, the LBD undergoes a major rearrangement, resulting in a separation of the four subunits by ∼25 Å. However, the amino terminal domain, transmembrane, and cytoplasmic regions of the receptor have similar conformations in the resting and desensitized states. The LBD rearrangement was not anticipated in prior models based on crystal structures for soluble LBD dimer assemblies, and we speculate that subunit separation allows a better match to the fourfold symmetric ion channel domain. From fits of the amino terminal domain and LBD domains into the density map of the desensitized state we have derived a structural model for differences in quaternary conformation between the resting and desensitized states.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

April 9, 2013

Volume

110

Issue

15

Start / End Page

5921 / 5926

Location

United States

Related Subject Headings

  • Tomography
  • Receptors, Kainic Acid
  • Rats
  • Protein Structure, Quaternary
  • Protein Interaction Domains and Motifs
  • Point Mutation
  • Models, Molecular
  • Ligands
  • Ion Channel Gating
  • GluK2 Kainate Receptor
 

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Schauder, D. M., Kuybeda, O., Zhang, J., Klymko, K., Bartesaghi, A., Borgnia, M. J., … Subramaniam, S. (2013). Glutamate receptor desensitization is mediated by changes in quaternary structure of the ligand binding domain. Proc Natl Acad Sci U S A, 110(15), 5921–5926. https://doi.org/10.1073/pnas.1217549110
Schauder, David M., Oleg Kuybeda, Jinjin Zhang, Katherine Klymko, Alberto Bartesaghi, Mario J. Borgnia, Mark L. Mayer, and Sriram Subramaniam. “Glutamate receptor desensitization is mediated by changes in quaternary structure of the ligand binding domain.Proc Natl Acad Sci U S A 110, no. 15 (April 9, 2013): 5921–26. https://doi.org/10.1073/pnas.1217549110.
Schauder DM, Kuybeda O, Zhang J, Klymko K, Bartesaghi A, Borgnia MJ, et al. Glutamate receptor desensitization is mediated by changes in quaternary structure of the ligand binding domain. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):5921–6.
Schauder, David M., et al. “Glutamate receptor desensitization is mediated by changes in quaternary structure of the ligand binding domain.Proc Natl Acad Sci U S A, vol. 110, no. 15, Apr. 2013, pp. 5921–26. Pubmed, doi:10.1073/pnas.1217549110.
Schauder DM, Kuybeda O, Zhang J, Klymko K, Bartesaghi A, Borgnia MJ, Mayer ML, Subramaniam S. Glutamate receptor desensitization is mediated by changes in quaternary structure of the ligand binding domain. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):5921–5926.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

April 9, 2013

Volume

110

Issue

15

Start / End Page

5921 / 5926

Location

United States

Related Subject Headings

  • Tomography
  • Receptors, Kainic Acid
  • Rats
  • Protein Structure, Quaternary
  • Protein Interaction Domains and Motifs
  • Point Mutation
  • Models, Molecular
  • Ligands
  • Ion Channel Gating
  • GluK2 Kainate Receptor