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- PDB-8bgi: GABA-A receptor a5 homomer - a5V1 - Flumazenil -

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Basic information

Entry
Database: PDB / ID: 8bgi
TitleGABA-A receptor a5 homomer - a5V1 - Flumazenil
ComponentsGamma-aminobutyric acid receptor subunit alpha-5
KeywordsMEMBRANE PROTEIN / pLGIC GABA Neurotransmission
Function / homology
Function and homology information


inner ear receptor cell development / GABA receptor binding / innervation / GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / neuronal cell body membrane / gamma-aminobutyric acid signaling pathway ...inner ear receptor cell development / GABA receptor binding / innervation / GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / neuronal cell body membrane / gamma-aminobutyric acid signaling pathway / postsynaptic specialization membrane / synaptic transmission, GABAergic / cochlea development / associative learning / chloride channel complex / behavioral fear response / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / dendrite membrane / chloride transmembrane transport / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / GABA-ergic synapse / signaling receptor activity / presynaptic membrane / postsynapse / signal transduction / nucleoplasm / plasma membrane / cytosol
Similarity search - Function
Gamma-aminobutyric-acid A receptor, alpha 5 subunit / Gamma-aminobutyric-acid A receptor, alpha subunit / : / Gamma-aminobutyric acid A receptor/Glycine receptor alpha / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor ...Gamma-aminobutyric-acid A receptor, alpha 5 subunit / Gamma-aminobutyric-acid A receptor, alpha subunit / : / Gamma-aminobutyric acid A receptor/Glycine receptor alpha / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily / Neurotransmitter-gated ion-channel ligand binding domain
Similarity search - Domain/homology
Chem-FYP / Pregnanolone / Gamma-aminobutyric acid receptor subunit alpha-5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.56 Å
AuthorsMiller, P.S. / Malinauskas, T.M. / Omari, K.E. / Aricescu, A.R.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Other private United Kingdom
CitationJournal: 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
DepositionOct 27, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Dec 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Gamma-aminobutyric acid receptor subunit alpha-5
B: Gamma-aminobutyric acid receptor subunit alpha-5
C: Gamma-aminobutyric acid receptor subunit alpha-5
D: Gamma-aminobutyric acid receptor subunit alpha-5
E: Gamma-aminobutyric acid receptor subunit alpha-5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)213,25250
Polymers206,0305
Non-polymers7,22245
Water41423
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)200.769, 131.641, 119.168
Angle α, β, γ (deg.)90.000, 100.190, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 15 through 73 or resid 75...
d_2ens_1(chain "B" and (resid 15 through 73 or resid 75...
d_3ens_1(chain "C" and (resid 15 through 73 or resid 75...
d_4ens_1(chain "D" and (resid 15 through 73 or resid 75...
d_5ens_1(chain "E" and (resid 15 through 73 or resid 75...

NCS domain segments:

Ens-ID: ens_1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ILEILETRPTRPAA15 - 7315 - 73
d_12ASPASPLYSLYSAA75 - 10875 - 108
d_13SERSERTHRTHRAA110 - 175110 - 175
d_14GLYGLYASNASNAA177 - 419177 - 349
d_21ILEILETRPTRPBB15 - 7315 - 73
d_22ASPASPLYSLYSBB75 - 10875 - 108
d_23SERSERTHRTHRBB110 - 175110 - 175
d_24GLYGLYASNASNBB177 - 419177 - 349
d_31ILEILETRPTRPCC15 - 7315 - 73
d_32ASPASPLYSLYSCC75 - 10875 - 108
d_33SERSERTHRTHRCC110 - 175110 - 175
d_34GLYGLYASNASNCC177 - 419177 - 349
d_41ILEILETRPTRPDD15 - 7315 - 73
d_42ASPASPLYSLYSDD75 - 10875 - 108
d_43SERSERTHRTHRDD110 - 175110 - 175
d_44GLYGLYASNASNDD177 - 419177 - 349
d_51ILEILETRPTRPEE15 - 7315 - 73
d_52ASPASPLYSLYSEE75 - 10875 - 108
d_53SERSERTHRTHREE110 - 175110 - 175
d_54GLYGLYASNASNEE177 - 419177 - 349

NCS oper:
IDCodeMatrixVector
1given(0.794933195305, -0.517940059811, -0.315941939991), (0.519040123246, 0.310952901772, 0.796181915984), (-0.314131446154, -0.796897977989, 0.516018456273)-0.365413755323, -63.4671879276, -0.706690745657
2given(0.463222669255, -0.320103094345, -0.826413194279), (0.324170218784, -0.806671412685, 0.494160805013), (-0.824826301679, -0.496805033135, -0.269900594868)32.4027470862, -83.9527099193, 49.5797298949
3given(0.460779073161, 0.321372361468, -0.827286196561), (-0.320459906525, -0.809007255412, -0.492760295682), (-0.827640075182, 0.492165689554, -0.269786656414)53.2421996554, -32.9803394516, 81.5695157967
4given(0.791819631997, 0.521709855139, -0.317553928389), (-0.520212705793, 0.30368869042, -0.798217965246), (-0.320000642367, 0.797240243817, 0.511866762471)33.2476311265, 18.8428903457, 50.9839940577

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Components

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Protein / Sugars , 2 types, 11 molecules ABCDE

#1: Protein
Gamma-aminobutyric acid receptor subunit alpha-5 / GABA(A) receptor subunit alpha-5


Mass: 41205.938 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GABRA5 / Production host: Homo sapiens (human) / References: UniProt: P31644
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 4 types, 62 molecules

#2: Chemical...
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 29 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-FYP / ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate / Flumazenil


Mass: 303.288 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C15H14FN3O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: antagonist*YM
#4: Chemical
ChemComp-P9N / Pregnanolone / (3alpha,5beta)-3-Hydroxypregnan-20-one


Mass: 318.493 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C21H34O2 / Comment: inhibitor*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.76 Å3/Da / Density % sol: 67.3 %
Crystal growTemperature: 279 K / Method: vapor diffusion, sitting drop
Details: 19 % PEG 1000 0.1 M sodium chloride 0.15 M ammonium sulfate 0.1 M 2-(N-morpholino)ethanesulfonic acid (MES) pH 6.5 25 mM Sucrose monodecanoate detergent (sucrose monocaprate)

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Data collection

DiffractionMean temperature: 298 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Nov 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.56→47.56 Å / Num. obs: 42005 / % possible obs: 92.2 % / Redundancy: 6.6 % / Biso Wilson estimate: 62.77 Å2 / CC1/2: 0.993 / Net I/σ(I): 7
Reflection shellResolution: 2.56→2.88 Å / Num. unique obs: 235 / CC1/2: 0.304

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Processing

Software
NameVersionClassification
REFMAC1.20.1_4487refinement
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4COF

4cof


Resolution: 2.56→47.56 Å / SU ML: 0.3889 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 37.7632
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2774 1641 4.84 %
Rwork0.2536 32295 -
obs0.2547 42005 92.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 68.35 Å2
Refinement stepCycle: LAST / Resolution: 2.56→47.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13525 0 454 23 14002
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002514330
X-RAY DIFFRACTIONf_angle_d0.490619553
X-RAY DIFFRACTIONf_chiral_restr0.03982184
X-RAY DIFFRACTIONf_plane_restr0.00382515
X-RAY DIFFRACTIONf_dihedral_angle_d9.56695244
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AX-RAY DIFFRACTIONTorsion NCS0.484013657894
ens_1d_3AX-RAY DIFFRACTIONTorsion NCS0.483213640904
ens_1d_4AX-RAY DIFFRACTIONTorsion NCS0.489534053224
ens_1d_5AX-RAY DIFFRACTIONTorsion NCS0.426521495241
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.83-2.910.652540.370167X-RAY DIFFRACTION1.17
2.91-3.010.5916140.3798330X-RAY DIFFRACTION5.78
3.01-3.110.3268240.3897601X-RAY DIFFRACTION10.38
3.11-3.240.4147380.3588905X-RAY DIFFRACTION15.62
3.24-3.390.369640.34381478X-RAY DIFFRACTION25.62
3.39-3.560.31011150.31442184X-RAY DIFFRACTION37.97
3.56-3.790.33281340.30122912X-RAY DIFFRACTION50.31
3.79-4.080.30061690.24163509X-RAY DIFFRACTION60.84
4.08-4.490.28352000.23464138X-RAY DIFFRACTION71.35
4.49-5.140.22692550.20824766X-RAY DIFFRACTION82.42
5.14-6.480.2792940.26975590X-RAY DIFFRACTION96.49
6.48-47.560.27043300.25035815X-RAY DIFFRACTION99.16
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.652218590290.251253260621-1.958101730410.893899531549-0.4276403515782.27898445712-0.04478031078670.507904963424-0.170284048756-0.465779918033-0.0467669433499-0.292463780736-0.0559692813156-0.2347989201310.06310001586870.612956052097-0.02666527712680.005693309766160.34797020502-0.01983806359120.34459615974230.3667616397-23.41577334969.37317336763
21.616742493210.0125156340835-1.442230411470.960924116340.1415167644132.01890210592-0.3353061648410.224637411209-0.53348397647-0.427941676152-0.0614368143469-0.4058002734250.4284777463560.001307836417480.2567724225070.6457858830610.03469634757420.06449366999250.380846829877-0.05557859472290.46113075934132.9461312536-47.526149900213.2540261972
30.682463217876-0.419091789171-0.5293181518750.5748941681290.1776653107291.08960887016-0.158746338319-0.578813136689-0.511533023563-0.154284789086-0.134844985058-0.5697899528650.2894649564220.8352529694640.189539035950.6436970894170.2968152583480.1631337131470.8279868324690.2997951915930.97684158002746.2113906128-50.593810711433.635523498
41.06879472431-0.200834922735-0.3476792419230.3873412399890.1914620893910.4758310108890.0772851830062-0.6707505419050.1370584887-0.07330402573320.0362036520855-0.760187506137-0.1410124994280.78324187428-0.07115263302280.4379581047510.0800942866444-0.2027999023841.24050104520.05368334788360.67422416933651.9558957172-28.384830830742.3865466748
51.855985181750.00567008488959-0.6669064147641.043398846320.174893911831.069769318020.388492050673-0.3367660469560.376388843424-0.317706265093-0.073451911027-0.589438788488-0.5767225956660.596430203592-0.2070094062460.549002621819-0.1493957140410.03553552244590.510909144174-0.0636344900940.58210414009942.0991371175-11.547435898527.3963787335
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth seq-ID: 15 - 419 / Label seq-ID: 1 - 335

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-ID
11(chain 'A' and resid 15 through 456)AA
22(chain 'B' and resid 15 through 456)BB
33(chain 'C' and resid 15 through 456)CC
44(chain 'D' and resid 15 through 456)DD
55(chain 'E' and resid 15 through 456)EE

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