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Open data
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Basic information
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Title | GABA-A receptor a5 homomer - a5V3 - RO5211223 | |||||||||
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![]() | pLGIC GABA Neurotransmission / MEMBRANE PROTEIN | |||||||||
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 / postsynaptic specialization membrane / gamma-aminobutyric acid signaling pathway / cochlea development / neuronal cell body membrane / associative learning / chloride channel complex / GABA-ergic synapse / transmembrane transporter complex / 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 | single particle reconstruction / cryo EM / Resolution: 2.67 Å | |||||||||
![]() | Miller PS / Malinauskas TM / Hardwick SW / Chirgadze DY | |||||||||
Funding support | ![]()
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![]() | ![]() 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. | |||||||||
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Structure visualization
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Downloads & links
-EMDB archive
Map data | ![]() | 267.2 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 14.7 KB 14.7 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 17.2 KB | Display | ![]() |
Images | ![]() | 163.2 KB | ||
Filedesc metadata | ![]() | 5.7 KB | ||
Others | ![]() ![]() | 497.3 MB 497.2 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 1.2 MB | Display | ![]() |
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Full document | ![]() | 1.2 MB | Display | |
Data in XML | ![]() | 26.9 KB | Display | |
Data in CIF | ![]() | 34.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8bhiMC ![]() 8bejC ![]() 8bgiC ![]() 8bhaC ![]() 8bhbC ![]() 8bhgC ![]() 8bhkC ![]() 8bhmC ![]() 8bhoC ![]() 8bhqC ![]() 8bhrC ![]() 8bhsC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.652 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_16055_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_16055_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : GABA-A receptor a5 homomer - a5V3 - RO5211223
Entire | Name: GABA-A receptor a5 homomer - a5V3 - RO5211223 |
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Components |
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-Supramolecule #1: GABA-A receptor a5 homomer - a5V3 - RO5211223
Supramolecule | Name: GABA-A receptor a5 homomer - a5V3 - RO5211223 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 205 KDa |
-Macromolecule #1: Gamma-aminobutyric acid receptor subunit alpha-5
Macromolecule | Name: Gamma-aminobutyric acid receptor subunit alpha-5 / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 41.05791 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: QMPTSSVKDE TNDNITIFTR ILDGLLDGYD NRLRPGLGER ITQVRTDMYV NSFGPVSDTE MEYTIDIFFA QTWKDERLRF KGPMQRLPL NNLLASKIWT PDTFFHNGKK SFAHWMTTPN RMLRIWNDGR VLYTLRLTIS AECPMDLEDF PMDEQNCPLK F GSYAYPNS ...String: QMPTSSVKDE TNDNITIFTR ILDGLLDGYD NRLRPGLGER ITQVRTDMYV NSFGPVSDTE MEYTIDIFFA QTWKDERLRF KGPMQRLPL NNLLASKIWT PDTFFHNGKK SFAHWMTTPN RMLRIWNDGR VLYTLRLTIS AECPMDLEDF PMDEQNCPLK F GSYAYPNS EVVYVWTNGS TKSVVVAEDG SRLNQYHLMG QTVGTENIST STGEYTIMTA HFHLKRKIGY FVIQTYLPCI MT VILSQVS FWLNRESVAA RTVFGVTTVL TMTTLSISAR NSLPKVAYAT AMDWFIAVCY AFVFSALLEF AFVNYITKSQ PAR AAKIDK MSRIVFPILF GTFNLVYWAT YLNGTTETSQ VAPA UniProtKB: Gamma-aminobutyric acid receptor subunit alpha-5, Gamma-aminobutyric acid receptor subunit alpha-5 |
-Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 5 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #3: [1,1-bis(oxidanylidene)-1,4-thiazinan-4-yl]-[6-[[5-methyl-3-(6-me...
Macromolecule | Name: [1,1-bis(oxidanylidene)-1,4-thiazinan-4-yl]-[6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone type: ligand / ID: 3 / Number of copies: 5 / Formula: QKF |
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Molecular weight | Theoretical: 442.488 Da |
Chemical component information | ![]() ChemComp-QKF: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 1.5 mg/mL |
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Buffer | pH: 7.4 |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average exposure time: 1.45 sec. / Average electron dose: 49.27 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: SPOT SCAN / Imaging mode: DIFFRACTION / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |