Pharmacological and structural characterization of conformationally restricted (S)-glutamate analogues at ionotropic glutamate receptors
| Autor: | Michael Gajhede, Raminta Venskutonytė, Zeinab Assaf, Darryl S. Pickering, Karla Frydenvang, Lennart Bunch, Lina Juknaitė, David J. Aitken, Sophie Faure, Thierry Gefflaut, Birgitte Nielsen, Jette S. Kastrup |
|---|---|
| Přispěvatelé: | Department of Drug Design and Pharmacology [Copenhagen] (ILF), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Agonist medicine.drug_class Stereochemistry Amino Acid Motifs Glycine Kainate receptor AMPA receptor Crystallography X-Ray 03 medical and health sciences 0302 clinical medicine Glutamates Receptors Kainic Acid Structural Biology medicine Animals Receptors AMPA Binding site 030304 developmental biology 0303 health sciences Binding Sites Chemistry AMPA Kainate Binding affinity Crystal structure Subtype selectivity Structure comparison Glutamate receptor Hydrogen Bonding Stereoisomerism Ligand (biochemistry) Rats NMDA receptor Cyclobutanes 030217 neurology & neurosurgery Protein Binding Ionotropic effect |
| Zdroj: | HAL Journal of Structural Biology Journal of Structural Biology, Elsevier, 2012, 180, pp.39-46 Journal of Structural Biology, 2012, 180, pp.39-46 |
| ISSN: | 1047-8477 1095-8657 |
| DOI: | 10.1016/j.jsb.2012.07.001 |
| Popis: | International audience; Conformationally restricted glutamate analogues have been pharmacologically characterized at AMPA and kainate receptors and the crystal structures have been solved of the ligand (2S,10R,20S)-2-(20-carboxycyclobutyl) glycine (CBG-IV) in complex with the ligand binding domains of the AMPA receptor GluA2 and the kainate receptor GluK3. These structures show that CBG-IV interacts with the binding pocket in the same way as (S)-glutamate. The binding affinities reveal that CBG-IV has high affinity at the AMPA and kainate receptor subtypes. Appreciable binding affinity of CBG-IV was not observed at NMDA receptors, where the introduction of the carbocyclic ring is expected to lead to a steric clash with binding site residues. CBG-IV was demonstrated to be an agonist at both GluA2 and the kainate receptor GluK1. CBG-IV showed high affinity binding to GluK1 compared to GluA2, GluK2 and GluK3, which exhibited lower affinity for CBG-IV. The structure of GluA2 LBD and GluK3 LBD in complex with CBG-IV revealed similar binding site interactions to those of (S)-glutamate. No major conformational rearrangements compared to the (S)-glutamate bound conformation were found in GluK3 in order to accommodate CBG-IV, in contrast with GluA2 where a shift in lobe D2 binding site residues occurs, leading to an increased binding cavity volume compared to the (S)-glutamate bound structure. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect