Correlating efficacy and desensitization with GluK2 ligand-binding domain movements

Nayeem, Naushaba; Mayans, Olga; Green, Tim

Correlating efficacy and desensitization with GluK2 ligand-binding domain movements

Dateien

Nayeem_0-350018.pdfGröße: 1.39 MBDownloads: 183

Datum

2013

Autor:innen

Nayeem, Naushaba

Mayans, Olga

Green, Tim

Open Access-Veröffentlichung

Open Access Gold

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Open Biology. 2013, 3(5), 130051. eISSN 2046-2441. Available under: doi: 10.1098/rsob.130051

Zusammenfassung

Gating of AMPA- and kainate-selective ionotropic glutamate receptors can be defined in terms of ligand affinity, efficacy and the rate and extent of desensitization. Crucial insights into all three elements have come from structural studies of the ligand-binding domain (LBD). In particular, binding-cleft closure is associated with efficacy, whereas dissociation of the dimer formed by neighbouring LBDs is linked with desensitization. We have explored these relationships in the kainate-selective subunit GluK2 by studying the effects of mutating two residues (K531 and R775) that form key contacts within the LBD dimer interface, but whose truncation unexpectedly attenuates desensitization. One mutation (K531A) also switches the relative efficacies of glutamate and kainate. LBD crystal structures incorporating these mutations revealed several conformational changes that together explain their phenotypes. K531 truncation results in new dimer contacts, consistent with slower desensitization and sideways movement in the ligand-binding cleft correlating with efficacy. The tested mutants also disrupted anion binding; no chloride was detected in the dimer-interface site, including in R775A where absence of chloride was the only structural change evident. From this, we propose that the charge balance in the GluK2 LBD dimer interface maintains a degree of instability, necessary for rapid and complete desensitization.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

kainate receptor, desensitization, agonistbinding domain, dimer interface, anion binding

Zitieren

ISO 690

NAYEEM, Naushaba, Olga MAYANS, Tim GREEN, 2013. Correlating efficacy and desensitization with GluK2 ligand-binding domain movements. In: Open Biology. 2013, 3(5), 130051. eISSN 2046-2441. Available under: doi: 10.1098/rsob.130051

BibTex

@article{Nayeem2013-05-29Corre-34987,
  year={2013},
  doi={10.1098/rsob.130051},
  title={Correlating efficacy and desensitization with GluK2 ligand-binding domain movements},
  number={5},
  volume={3},
  journal={Open Biology},
  author={Nayeem, Naushaba and Mayans, Olga and Green, Tim},
  note={Article Number: 130051}
}

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