[English] 日本語
Yorodumi Papers
- Database of articles cited by EMDB/PDB/SASBDB data -

+
Search query

Keywords
Structure methods
Author
Journal
IF

-
Structure paper

TitleSmall-molecule positive allosteric modulation of homomeric kainate receptors GluK1-3: development of screening assays and insight into GluK3 structure.
Journal, issue, pagesFEBS J, Vol. 291, Issue 7, Page 1506-1529, Year 2024
Publish dateFeb 23, 2024
AuthorsYasmin Bay / Raminta Venskutonytė / Stine M Frantsen / Thor S Thorsen / Maria Musgaard / Karla Frydenvang / Pierre Francotte / Bernard Pirotte / Philip C Biggin / Anders S Kristensen / Thomas Boesen / Darryl S Pickering / Michael Gajhede / Jette S Kastrup /
PubMed AbstractThe kainate receptors GluK1-3 (glutamate receptor ionotropic, kainate receptors 1-3) belong to the family of ionotropic glutamate receptors and are essential for fast excitatory neurotransmission in ...The kainate receptors GluK1-3 (glutamate receptor ionotropic, kainate receptors 1-3) belong to the family of ionotropic glutamate receptors and are essential for fast excitatory neurotransmission in the brain, and are associated with neurological and psychiatric diseases. How these receptors can be modulated by small-molecule agents is not well understood, especially for GluK3. We show that the positive allosteric modulator BPAM344 can be used to establish robust calcium-sensitive fluorescence-based assays to test agonists, antagonists, and positive allosteric modulators of GluK1-3. The half-maximal effective concentration (EC) of BPAM344 for potentiating the response of 100 μm kainate was determined to be 26.3 μm for GluK1, 75.4 μm for GluK2, and 639 μm for GluK3. Domoate was found to be a potent agonist for GluK1 and GluK2, with an EC of 0.77 and 1.33 μm, respectively, upon co-application of 150 μm BPAM344. At GluK3, domoate acts as a very weak agonist or antagonist with a half-maximal inhibitory concentration (IC) of 14.5 μm, in presence of 500 μm BPAM344 and 100 μm kainate for competition binding. Using H523A-mutated GluK3, we determined the first dimeric structure of the ligand-binding domain by X-ray crystallography, allowing location of BPAM344, as well as zinc-, sodium-, and chloride-ion binding sites at the dimer interface. Molecular dynamics simulations support the stability of the ion sites as well as the involvement of Asp761, Asp790, and Glu797 in the binding of zinc ions. Using electron microscopy, we show that, in presence of glutamate and BPAM344, full-length GluK3 adopts a dimer-of-dimers arrangement.
External linksFEBS J / PubMed:38145505
MethodsEM (single particle) / X-ray diffraction
Resolution2.7 - 6.61 Å
Structure data

EMDB-15985: Small molecule positive allosteric modulation of homomeric kainate receptors GluK1-3: Development of screening assays and insight into GluK3 structure
Method: EM (single particle) / Resolution: 6.6 Å

EMDB-15986: Ionotropic glutamate receptor K3 with glutamate and BPAM
Method: EM (single particle) / Resolution: 6.61 Å

PDB-8bst:
Crystal structure of the kainate receptor GluK3-H523A ligand binding domain in complex with kainate at 2.7A resolution
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

PDB-8bsu:
Crystal structure of the kainate receptor GluK3-H523A ligand binding domain in complex with kainate and the positive allosteric modulator BPAM344 at 2.9A resolution
Method: X-RAY DIFFRACTION / Resolution: 2.9 Å

Chemicals

ChemComp-ACT:
ACETATE ION

ChemComp-ZN:
Unknown entry

ChemComp-CL:
Unknown entry

ChemComp-SO4:
SULFATE ION

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER

ChemComp-KAI:
3-(CARBOXYMETHYL)-4-ISOPROPENYLPROLINE / neurotransmitter, agonist*YM

ChemComp-GOL:
GLYCEROL

ChemComp-HOH:
WATER

ChemComp-2J9:
4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide

Source
  • Homo sapiens (human)
  • rattus norvegicus (Norway rat)
KeywordsMEMBRANE PROTEIN / IONOTROPIC GLUTAMATE RECEPTOR / GLUK3 LIGAND-BINDING DOMAIN / GluK3-M523A-LBD / GluK3-H523A-LBD / positive allosteric modulator / BPAM344

+
About Yorodumi Papers

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi Papers

Database of articles cited by EMDB/PDB/SASBDB data

  • Database of articles cited by EMDB, PDB, and SASBDB entries
  • Using PubMed data

Related info.:EMDB / PDB / SASBDB / Yorodumi / EMN Papers / Changes in new EM Navigator and Yorodumi

Read more