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- EMDB-14069: Cryo-EM structure of human full-length extrasynaptic alpha4beta3d... -
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Open data
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Basic information
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Title | Cryo-EM structure of human full-length extrasynaptic alpha4beta3delta GABA(A)R in complex with GABA, histamine and nanobody Nb25 | ||||||||||||||||||
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![]() | pentameric ligand-gated ion channel / neurotransmitter receptor / GABA receptor / MEMBRANE PROTEIN | ||||||||||||||||||
Function / homology | ![]() benzodiazepine receptor activity / cellular response to histamine / GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / Signaling by ERBB4 / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway ...benzodiazepine receptor activity / cellular response to histamine / GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / Signaling by ERBB4 / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway / postsynaptic specialization membrane / neurotransmitter receptor activity / chloride channel activity / roof of mouth development / chloride channel complex / transmembrane transporter complex / GABA-ergic synapse / regulation of postsynaptic membrane potential / chloride transmembrane transport / dendrite membrane / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / cytoplasmic vesicle membrane / postsynaptic membrane / postsynapse / neuron projection / axon / neuronal cell body / synapse / dendrite / signal transduction / identical protein binding / plasma membrane Similarity search - Function | ||||||||||||||||||
Biological species | ![]() | ||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.0 Å | ||||||||||||||||||
![]() | Sente A / Desai R | ||||||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Differential assembly diversifies GABA receptor structures and signalling. Authors: Andrija Sente / Rooma Desai / Katerina Naydenova / Tomas Malinauskas / Youssef Jounaidi / Jonas Miehling / Xiaojuan Zhou / Simonas Masiulis / Steven W Hardwick / Dimitri Y Chirgadze / Keith ...Authors: Andrija Sente / Rooma Desai / Katerina Naydenova / Tomas Malinauskas / Youssef Jounaidi / Jonas Miehling / Xiaojuan Zhou / Simonas Masiulis / Steven W Hardwick / Dimitri Y Chirgadze / Keith W Miller / A Radu Aricescu / ![]() ![]() ![]() Abstract: Type A γ-aminobutyric acid receptors (GABARs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits and can be modulated by essential medicines ...Type A γ-aminobutyric acid receptors (GABARs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits and can be modulated by essential medicines including general anaesthetics and benzodiazepines. Human GABAR subunits are encoded by 19 paralogous genes that can, in theory, give rise to 495,235 receptor types. However, the principles that govern the formation of pentamers, the permutational landscape of receptors that may emerge from a subunit set and the effect that this has on GABAergic signalling remain largely unknown. Here we use cryogenic electron microscopy to determine the structures of extrasynaptic GABARs assembled from α4, β3 and δ subunits, and their counterparts incorporating γ2 instead of δ subunits. In each case, we identified two receptor subtypes with distinct stoichiometries and arrangements, all four differing from those previously observed for synaptic, α1-containing receptors. This, in turn, affects receptor responses to physiological and synthetic modulators by creating or eliminating ligand-binding sites at subunit interfaces. We provide structural and functional evidence that selected GABAR arrangements can act as coincidence detectors, simultaneously responding to two neurotransmitters: GABA and histamine. Using assembly simulations and single-cell RNA sequencing data, we calculated the upper bounds for receptor diversity in recombinant systems and in vivo. We propose that differential assembly is a pervasive mechanism for regulating the physiology and pharmacology of GABARs. | ||||||||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 77.2 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 20 KB 20 KB | Display Display | ![]() |
Images | ![]() | 72.7 KB | ||
Filedesc metadata | ![]() | 7.3 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 522.9 KB | Display | ![]() |
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Full document | ![]() | 522.5 KB | Display | |
Data in XML | ![]() | 6.4 KB | Display | |
Data in CIF | ![]() | 7.3 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7qn7MC ![]() 7qn5C ![]() 7qn6C ![]() 7qn8C ![]() 7qn9C ![]() 7qnaC ![]() 7qnbC ![]() 7qncC ![]() 7qndC ![]() 7qneC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
EM raw data | ![]() Data size: 2.8 TB Data #1: Unaligned multi-frame micrographs of GABA(A)Rs purified from cells epxressing human full-length alpha4, beta3 and delta subunits, in presence of GABA, histamine, Ro15-4513 and nanobody Nb25 ...Data #1: Unaligned multi-frame micrographs of GABA(A)Rs purified from cells epxressing human full-length alpha4, beta3 and delta subunits, in presence of GABA, histamine, Ro15-4513 and nanobody Nb25 [micrographs - multiframe]) ![]() Data size: 3.0 TB Data #1: Unaligned multi-frame micrographs of GABA(A) receptors purified from cells expressing human full-length alpha4, beta3 and delta subunits, in presence of GABA, histamine and nanobody Nb25 ...Data #1: Unaligned multi-frame micrographs of GABA(A) receptors purified from cells expressing human full-length alpha4, beta3 and delta subunits, in presence of GABA, histamine and nanobody Nb25 [micrographs - multiframe]) |
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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: 0.896 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
+Entire : Human full-length extrasynaptic alpha4beta3delta GABA(A)R in comp...
+Supramolecule #1: Human full-length extrasynaptic alpha4beta3delta GABA(A)R in comp...
+Macromolecule #1: Gamma-aminobutyric acid receptor subunit alpha-4
+Macromolecule #2: Gamma-aminobutyric acid receptor subunit beta-3
+Macromolecule #3: Gamma-aminobutyric acid receptor subunit delta
+Macromolecule #4: Nanobody Nb25
+Macromolecule #7: 1,2-DIPALMITOYL-SN-GLYCERO-3-PHOSPHATE
+Macromolecule #8: DECANE
+Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose
+Macromolecule #10: GAMMA-AMINO-BUTANOIC ACID
+Macromolecule #11: HEXADECANE
+Macromolecule #12: HISTAMINE
+Macromolecule #13: water
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.6 Component:
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Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 287 K / Instrument: LEICA PLUNGER |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.1 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 130000 |
Sample stage | Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Refinement | Protocol: AB INITIO MODEL |
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Output model | ![]() PDB-7qn7: |