+
Open data
-
Basic information
Entry | Database: PDB / ID: 8bhq | ||||||
---|---|---|---|---|---|---|---|
Title | GABA-A receptor a5 homomer - a5V3 - RO7172670 | ||||||
![]() | Gamma-aminobutyric acid receptor subunit alpha-5 | ||||||
![]() | MEMBRANE PROTEIN / pLGIC GABA Neurotransmission | ||||||
Function / homology | ![]() inhibitory extracellular ligand-gated monoatomic ion channel activity / benzodiazepine receptor activity / GABA receptor activation / inner ear receptor cell development / GABA-gated chloride ion channel activity / GABA-A receptor activity / GABA-A receptor complex / GABA receptor binding / inhibitory synapse assembly / innervation ...inhibitory extracellular ligand-gated monoatomic ion channel activity / benzodiazepine receptor activity / GABA receptor activation / inner ear receptor cell development / GABA-gated chloride ion channel activity / GABA-A receptor activity / GABA-A receptor complex / GABA receptor binding / inhibitory synapse assembly / innervation / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway / postsynaptic specialization membrane / neuronal cell body membrane / cochlea development / associative learning / chloride channel complex / transmembrane transporter complex / GABA-ergic synapse / behavioral fear response / regulation of postsynaptic membrane potential / chloride transmembrane transport / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / presynaptic membrane / signaling receptor activity / postsynapse / neuron projection / synapse / signal transduction / nucleoplasm / plasma membrane / cytosol Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||
![]() | Miller, P.S. / Malinauskas, T.M. / Hardwick, S.W. / Kasaragod, V.B. | ||||||
Funding support | ![]()
| ||||||
![]() | ![]() 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 |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 635.7 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | 541.1 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.7 MB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 1.7 MB | Display | |
Data in XML | ![]() | 56.6 KB | Display | |
Data in CIF | ![]() | 83 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 16066MC ![]() 8bejC ![]() 8bgiC ![]() 8bhaC ![]() 8bhbC ![]() 8bhgC ![]() 8bhiC ![]() 8bhkC ![]() 8bhmC ![]() 8bhoC ![]() 8bhrC ![]() 8bhsC M: map data used to model this data C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
#1: Protein | Mass: 41057.910 Da / Num. of mol.: 5 Mutation: I79M,T82N,V98I,R101A,S103T,I142F,N145W,K151R,L152M,L155I,E156W,D157N,T160R,L161V,M165L,Q176D,A184E,H185Q,A186N,P287A,I336L,T340F,F344I,V335I Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #2: Sugar | ChemComp-NAG / #3: Chemical | ChemComp-QR3 / Has ligand of interest | Y | |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-
Sample preparation
Component | Name: GABA-A a5 subunit of homopentamer complex called a5V3 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
---|---|
Molecular weight | Value: 0.205 MDa / Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-
Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: DIFFRACTION / Nominal defocus max: 2500 nm / Nominal defocus min: 900 nm |
Image recording | Electron dose: 50.8 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-
Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
---|---|
3D reconstruction | Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 35250 / Symmetry type: POINT |