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- PDB-4u4x: Crystal structure of the GluA2 ligand-binding domain (S1S2J-L483Y... -

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Basic information

Entry
Database: PDB / ID: 4u4x
TitleCrystal structure of the GluA2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and BPAM37 at 1.56 A resolution.
ComponentsGlutamate receptor 2,Glutamate receptor 2
KeywordsMEMBRANE PROTEIN / AMPA RECEPTOR LIGAND-BINDING DOMAIN / BPAM37 ALLOSTERIC MODULATION
Function / homology
Function and homology information


spine synapse / dendritic spine neck / dendritic spine head / cellular response to amine stimulus / perisynaptic space / Activation of AMPA receptors / ligand-gated monoatomic cation channel activity / AMPA glutamate receptor activity / response to lithium ion / Trafficking of GluR2-containing AMPA receptors ...spine synapse / dendritic spine neck / dendritic spine head / cellular response to amine stimulus / perisynaptic space / Activation of AMPA receptors / ligand-gated monoatomic cation channel activity / AMPA glutamate receptor activity / response to lithium ion / Trafficking of GluR2-containing AMPA receptors / kainate selective glutamate receptor activity / cellular response to glycine / AMPA glutamate receptor complex / extracellularly glutamate-gated ion channel activity / immunoglobulin binding / asymmetric synapse / ionotropic glutamate receptor complex / conditioned place preference / regulation of receptor recycling / glutamate receptor binding / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of synaptic transmission / regulation of synaptic transmission, glutamatergic / response to fungicide / cytoskeletal protein binding / glutamate-gated receptor activity / regulation of long-term synaptic depression / cellular response to brain-derived neurotrophic factor stimulus / extracellular ligand-gated monoatomic ion channel activity / glutamate-gated calcium ion channel activity / presynaptic active zone membrane / somatodendritic compartment / dendrite membrane / ionotropic glutamate receptor binding / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / synaptic membrane / dendritic shaft / SNARE binding / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / PDZ domain binding / protein tetramerization / establishment of protein localization / postsynaptic density membrane / cerebral cortex development / modulation of chemical synaptic transmission / receptor internalization / Schaffer collateral - CA1 synapse / terminal bouton / synaptic vesicle / synaptic vesicle membrane / signaling receptor activity / presynapse / amyloid-beta binding / growth cone / presynaptic membrane / scaffold protein binding / perikaryon / dendritic spine / chemical synaptic transmission / postsynaptic membrane / neuron projection / postsynaptic density / axon / external side of plasma membrane / neuronal cell body / synapse / dendrite / protein kinase binding / protein-containing complex binding / glutamatergic synapse / cell surface / endoplasmic reticulum / protein-containing complex / identical protein binding / membrane / plasma membrane
Similarity search - Function
Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region ...Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like II / Periplasmic binding protein-like I / D-Maltodextrin-Binding Protein; domain 2 / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-3C2 / ACETATE ION / GLUTAMIC ACID / DI(HYDROXYETHYL)ETHER / Glutamate receptor 2
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.56 Å
AuthorsNoerholm, A.B. / Frydenvang, K. / Kastrup, J.S.
Citation
Journal: J.Med.Chem. / Year: 2014
Title: Positive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely ...Title: Positive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides.
Authors: Francotte, P. / Nrholm, A.B. / Deva, T. / Olsen, L. / Frydenvang, K. / Goffin, E. / Fraikin, P. / de Tullio, P. / Challal, S. / Thomas, J.Y. / Iop, F. / Louis, C. / Botez-Pop, I. / Lestage, ...Authors: Francotte, P. / Nrholm, A.B. / Deva, T. / Olsen, L. / Frydenvang, K. / Goffin, E. / Fraikin, P. / de Tullio, P. / Challal, S. / Thomas, J.Y. / Iop, F. / Louis, C. / Botez-Pop, I. / Lestage, P. / Danober, L. / Kastrup, J.S. / Pirotte, B.
#1: Journal: J. Med. Chem. / Year: 2013
Title: Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold.
Authors: Noerholm, A.B. / Francotte, P. / Olsen, L. / Krintel, C. / Frydenvang, K. / Goffin, E. / Challal, S. / Danober, L. / Botez-Pop, I. / Lestage, P. / Pirotte, B. / Kastrup, J.S.
#2: Journal: Biochem. J. / Year: 2012
Title: Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2.
Authors: Krintel, C. / Frydenvang, K. / Olsen, L. / Kristensen, M.T. / de Barrios, O. / Naur, P. / Francotte, P. / Pirotte, B. / Gajhede, M. / Kastrup, J.S.
History
DepositionJul 24, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Nov 19, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 10, 2014Group: Database references
Revision 1.2Jan 17, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.3Dec 20, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glutamate receptor 2,Glutamate receptor 2
B: Glutamate receptor 2,Glutamate receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,41520
Polymers58,4892
Non-polymers1,92618
Water10,629590
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5100 Å2
ΔGint-77 kcal/mol
Surface area23810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.290, 121.569, 47.360
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Glutamate receptor 2,Glutamate receptor 2 / AMPA 2 / GluA2


Mass: 29244.678 Da / Num. of mol.: 2 / Fragment: UNP residues 413-527, UNP residues 653-796 / Mutation: yes
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gria2, Glur2 / Plasmid: pET-22b(+) / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): ORIGAMI 2 / References: UniProt: P19491

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Non-polymers , 7 types, 608 molecules

#2: Chemical ChemComp-3C2 / 4-ethyl-3,4-dihydro-2H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide


Mass: 213.257 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H11N3O2S
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H9NO4
#5: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 590 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.42 Å3/Da / Density % sol: 49.15 %
Crystal growTemperature: 280 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 24% PEG4000, 0.1 M ammoniumsulfate, 0.1 M phosphate-citrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I911-3 / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jan 24, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.56→121.569 Å / Num. all: 81474 / Num. obs: 81474 / % possible obs: 99.8 % / Redundancy: 3.8 % / Biso Wilson estimate: 16.12 Å2 / Rpim(I) all: 0.025 / Rrim(I) all: 0.051 / Rsym value: 0.044 / Net I/av σ(I): 10.059 / Net I/σ(I): 14.5 / Num. measured all: 310291
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
1.56-1.643.80.3411.844476117660.2020.3413.5100
1.64-1.743.80.2223.542565111660.1290.2224.9100
1.74-1.863.80.1414.540117104850.0820.1417.1100
1.86-2.013.80.0937.13750298070.0540.09310.9100
2.01-2.213.80.05712.13478290490.0330.05715.8100
2.21-2.473.80.0515.83125882220.0310.05119.6100
2.47-2.853.80.03912.82764872720.0230.03923.3100
2.85-3.493.80.03217.62362761720.0180.03229.299.8
3.49-4.933.80.02423.41846548340.0130.0243599.3
4.93-29.0363.60.01930985127010.0110.01931.496.5

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Processing

Software
NameVersionClassification
SCALA3.3.15data scaling
PHASERphasing
PDB_EXTRACT3.14data extraction
PHENIX(phenix.refine: 1.8.4_1496)refinement
Cootmodel building
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1LB8, molA

1lb8


Resolution: 1.56→29.036 Å / FOM work R set: 0.8946 / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 17.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1749 4083 5.02 %
Rwork0.1497 77304 -
obs0.151 81387 99.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 111.9 Å2 / Biso mean: 24.98 Å2 / Biso min: 9.12 Å2
Refinement stepCycle: final / Resolution: 1.56→29.036 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4072 0 192 590 4854
Biso mean--40.49 33.23 -
Num. residues----522
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.014338
X-RAY DIFFRACTIONf_angle_d1.2525843
X-RAY DIFFRACTIONf_chiral_restr0.049635
X-RAY DIFFRACTIONf_plane_restr0.006726
X-RAY DIFFRACTIONf_dihedral_angle_d12.5921663
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 29

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.56-1.57840.24461500.212626472797100
1.5784-1.59760.20541100.202526312741100
1.5976-1.61780.23031270.196426552782100
1.6178-1.63910.25211370.184626582795100
1.6391-1.66160.2151360.185726252761100
1.6616-1.68530.21841510.178526422793100
1.6853-1.71040.22961280.173426322760100
1.7104-1.73720.19151590.16526262785100
1.7372-1.76560.1991370.161926472784100
1.7656-1.79610.18261340.162226602794100
1.7961-1.82870.16171390.159626362775100
1.8287-1.86390.20761150.1626702785100
1.8639-1.90190.1741640.166126572821100
1.9019-1.94330.19791420.161926172759100
1.9433-1.98850.17631270.161426822809100
1.9885-2.03820.20071400.154926462786100
2.0382-2.09330.18411340.146826842818100
2.0933-2.15490.16821630.144526452808100
2.1549-2.22440.16311400.141326562796100
2.2244-2.30390.17311410.149426532794100
2.3039-2.39610.15411490.139526722821100
2.3961-2.50510.18711520.140526832835100
2.5051-2.63710.15421430.143526812824100
2.6371-2.80220.17151490.143826722821100
2.8022-3.01830.17661230.148827122835100
3.0183-3.32170.17691590.142926862845100
3.3217-3.80140.15231400.13882714285499
3.8014-4.78590.14341520.11822723287599
4.7859-29.04090.18321420.16332792293496
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)
12.15060.044-0.29561.555-0.33162.10490.0978-0.050.2076-0.0788-0.0049-0.1192-0.31240.1551-0.06830.1505-0.03190.03340.0964-0.01350.1358-19.81716.944314.5713
24.5745-0.0087-0.83281.87380.07822.91920.08190.18240.0263-0.1296-0.0010.2499-0.1001-0.339-0.08140.11280.037-0.00840.09790.02080.0967-32.1095-1.13368.1817
30.4683-0.0149-0.38840.5655-0.08572.26420.00080.0199-0.0122-0.05230.00150.01370.0059-0.06560.00340.09040.001-0.00940.0914-0.00340.1203-28.8201-8.89919.0662
42.85160.6676-0.98523.56560.20163.2326-0.08660.1555-0.25250.04760.00030.22640.223-0.25270.0680.0561-0.0217-0.00180.1319-0.01920.1823-40.8468-13.554227.262
53.54690.3292-0.52461.63110.24021.52480.00920.0882-0.021-0.0254-0.04180.62610.111-0.31570.02480.068-0.0159-0.00180.1652-0.00980.232-45.2998-10.984426.2668
64.14141.5065-1.443.486-0.49644.3730.1679-0.03050.20320.3501-0.06760.3781-0.3128-0.3473-0.08240.12360.02730.0260.108-0.00810.1841-38.99620.843934.3375
71.1868-0.7553-1.14053.35411.75912.9238-0.0354-0.10630.03530.2020.1352-0.16540.00740.1526-0.10520.1080.0055-0.01210.11440.00680.1071-29.0825-5.383232.3924
82.9097-0.84630.8532.1536-0.89794.11180.01510.31920.0244-0.2037-0.0715-0.1590.06720.30610.02970.11160.00730.01980.0894-0.02080.1252-16.4818-8.9549.9482
92.8778-1.8395-4.8443.07813.33118.1793-0.0227-0.47580.15520.16990.2653-0.15080.05240.6363-0.26640.1256-0.0116-0.02830.2085-0.02950.1907-15.0403-0.647529.0641
101.56390.5737-0.08352.720.56220.65520.0148-0.0186-0.1431-0.031-0.0949-0.08110.10210.01240.0420.23490.04050.04050.11030.00190.1097-15.5131-39.468816.0992
111.2154-0.45370.32143.0153-0.69752.00010.01680.0844-0.1246-0.1696-0.06770.18140.07270.01430.00560.2243-0.01270.01110.0927-0.00540.1181-21.5944-40.206414.6172
121.24470.30320.09971.03270.13361.8611-0.0280.02890.0136-0.1251-0.0317-0.1180.22340.30180.0350.15150.06290.02890.14250.03080.1162-8.5434-26.677414.2107
132.8525-0.4014-0.33882.0472-0.72592.024-0.0412-0.31550.01770.1206-0.2845-0.45310.20130.59080.17110.14090.0645-0.00170.32570.08140.2197-1.12-24.3729.4585
142.5864-0.19610.21792.1117-0.00692.6958-0.03290.27960.1164-0.2478-0.00790.07560.13510.06590.03550.14180.0078-0.00530.07920.02080.0998-21.826-23.34789.3906
153.2725-0.13151.55332.6899-1.37594.64720.0052-0.3806-0.14390.37480.0236-0.0510.2453-0.0157-0.16050.2509-0.00340.04050.13950.02090.1345-24.4918-31.574227.7977
161.1378-0.3344-0.11890.87680.14220.7899-0.0518-0.0203-0.0060.01790.028-0.00780.08960.10360.03120.1283-0.00520.00330.12090.00570.0573-19.4388-16.363419.4729
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 47 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 48 through 79 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 80 through 123 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 124 through 152 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 153 through 173 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 174 through 187 )A0
7X-RAY DIFFRACTION7chain 'A' and (resid 188 through 217 )A0
8X-RAY DIFFRACTION8chain 'A' and (resid 218 through 244 )A0
9X-RAY DIFFRACTION9chain 'A' and (resid 245 through 263 )A0
10X-RAY DIFFRACTION10chain 'B' and (resid 4 through 22 )B0
11X-RAY DIFFRACTION11chain 'B' and (resid 23 through 47 )B0
12X-RAY DIFFRACTION12chain 'B' and (resid 48 through 123 )B0
13X-RAY DIFFRACTION13chain 'B' and (resid 124 through 217 )B0
14X-RAY DIFFRACTION14chain 'B' and (resid 218 through 243 )B0
15X-RAY DIFFRACTION15chain 'B' and (resid 244 through 262 )B0
16X-RAY DIFFRACTION16chain 'C' and (resid 1 through 2 )C0

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