+Open data
-Basic information
Entry | Database: PDB / ID: 8bhg | ||||||
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Title | GABA-A receptor a5 heteromer - a5V2 - Bretazenil | ||||||
Components | (Gamma-aminobutyric acid receptor subunit ...) x 2 | ||||||
Keywords | MEMBRANE PROTEIN / pLGIC GABA Neurotransmission | ||||||
Function / homology | Function and homology information benzodiazepine receptor activity / inner ear receptor cell development / cellular response to histamine / GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / GABA receptor binding / inhibitory synapse assembly / innervation ...benzodiazepine receptor activity / inner ear receptor cell development / cellular response to histamine / GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / GABA receptor binding / inhibitory synapse assembly / innervation / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway / postsynaptic specialization membrane / neurotransmitter receptor activity / adult behavior / chloride channel activity / cochlea development / neuronal cell body membrane / Signaling by ERBB4 / associative learning / chloride channel complex / regulation of postsynaptic membrane potential / transmembrane transporter complex / behavioral fear response / GABA-ergic synapse / chloride transmembrane transport / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / post-embryonic development / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / cytoplasmic vesicle membrane / signaling receptor activity / presynaptic membrane / postsynaptic membrane / postsynapse / dendritic spine / neuron projection / axon / synapse / signal transduction / nucleoplasm / plasma membrane / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.39 Å | ||||||
Authors | Miller, P.S. / Malinauskas, T.M. / Omari, K.E. / Aricescu, A.R. | ||||||
Funding support | United Kingdom, 1items
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Citation | Journal: Nat Struct Mol Biol / Year: 2023 Title: The molecular basis of drug selectivity for α5 subunit-containing GABA receptors. Authors: Vikram Babu Kasaragod / Tomas Malinauskas / Ayla A Wahid / Judith Lengyel / Frederic Knoflach / Steven W Hardwick / Charlotte F Jones / Wan-Na Chen / Xavier Lucas / Kamel El Omari / Dimitri ...Authors: Vikram Babu Kasaragod / Tomas Malinauskas / Ayla A Wahid / Judith Lengyel / Frederic Knoflach / Steven W Hardwick / Charlotte F Jones / Wan-Na Chen / Xavier Lucas / Kamel El Omari / Dimitri Y Chirgadze / A Radu Aricescu / Giuseppe Cecere / Maria-Clemencia Hernandez / Paul S Miller / Abstract: α5 subunit-containing γ-aminobutyric acid type A (GABA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to ...α5 subunit-containing γ-aminobutyric acid type A (GABA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the α5 subunit. These define the molecular basis of binding and α5 selectivity of the β-carboline, methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appears as an 'upper' and 'lower' moiety in the pocket. Structural data and radioligand binding data reveal a positional displacement of the upper moiety containing the isoxazole between the NAMs and PAMs. Using a hybrid molecule we directly measure the functional contribution of the upper moiety to NAM versus PAM activity. Overall, these structures provide a framework by which to understand distinct modulator binding modes and their basis of α5-subtype selectivity, appreciate structure-activity relationships, and empower future structure-based drug design campaigns. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8bhg.cif.gz | 1.2 MB | Display | PDBx/mmCIF format |
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PDB format | pdb8bhg.ent.gz | 849.5 KB | Display | PDB format |
PDBx/mmJSON format | 8bhg.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8bhg_validation.pdf.gz | 3.1 MB | Display | wwPDB validaton report |
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Full document | 8bhg_full_validation.pdf.gz | 3.1 MB | Display | |
Data in XML | 8bhg_validation.xml.gz | 60.5 KB | Display | |
Data in CIF | 8bhg_validation.cif.gz | 80.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/bh/8bhg ftp://data.pdbj.org/pub/pdb/validation_reports/bh/8bhg | HTTPS FTP |
-Related structure data
Related structure data | 8bejC 8bgiC 8bhaC 8bhbC 8bhiC 8bhkC 8bhmC 8bhoC 8bhqC 8bhrC 8bhsC 4cofS S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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Noncrystallographic symmetry (NCS) | NCS domain:
NCS domain segments:
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