Structural analysis and thermodynamics of the ionotropic glutamate receptor GluA2 modulator BPAM-97

Research output: Contribution to conferencePoster

Abstract

Ionotropic glutamate receptors are tetrameric ligand gated ion channels that mediate in ux and ef ux of metal ions in response to glutamate. Positive allosteric modulators of the ionotropic glutamate receptor 2 (GluA2) are promising lead compounds for drugs against cognitive disorders. These compounds bind within the dimeric interface formed by the receptor ligand binding domains (LBDs) attenuating deactivation and desensitisation. In this study we determined the structure of the complex formed between a dimeric GluA2 LBD-L483Y-N754S mutant and the potent novel modulator BPAM-97 by X-ray crystallography. We provide a molecular explanation for the 200 fold increased potency of BPAM-97 compared to its parent compound IDRA-21. We also utilized isothermal titration calorimetry to measure the binding af nity and thermodynamics of the LBD-L483Y-N754S:BPAM-97 complex formation as well as that for the non-dimeric LBD-N754S:BPAM-97.

Details

Authors
  • Christian Krintel
  • Karla Frydenvang
  • Lars Olsen
  • Maria T Kristensen
  • Oriol de Barrios
  • Peter Naur
  • Pierre Francotte
  • Bernard Pirotte
  • Michael Gajhede
Organisations
External organisations
  • University of Copenhagen
  • University of Liège
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical and Health Sciences
  • Biophysics
Original languageEnglish
PagesP58
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedNo
EventMembrane Proteins: Structure and Function MGMS Spring Meeting - Oxford , United Kingdom
Duration: 2011 Apr 72011 Apr 9

Conference

ConferenceMembrane Proteins: Structure and Function MGMS Spring Meeting
Abbreviated titleMGMS
CountryUnited Kingdom
CityOxford
Period2011/04/072011/04/09

Related research output

Christian Krintel, Frydenvang, K., Olsen, L., Kristensen, M. T., de Barrios, O., Naur, P., Francotte, P., Pirotte, B., Gajhede, M. & Kastrup, J. S., 2012, In : Biochemical Journal. 441, 1, p. 173-178

Research output: Contribution to journalArticle

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