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- PDB-5tp9: Structure of the human GluN1/GluN2A LBD in complex with compound ... -

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Basic information

Entry
Database: PDB / ID: 5tp9
TitleStructure of the human GluN1/GluN2A LBD in complex with compound 2 (GNE9178)
Components(Glutamate receptor ionotropic, NMDA ...) x 2
KeywordsTRANSPORT PROTEIN / NMDA receptor / glutamate / glycine / calcium channel / membrane
Function / homology
Function and homology information


glycine-gated cation channel activity / excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / serotonin metabolic process / protein localization to postsynaptic membrane / sleep / response to glycine / propylene metabolic process / regulation of monoatomic cation transmembrane transport ...glycine-gated cation channel activity / excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / serotonin metabolic process / protein localization to postsynaptic membrane / sleep / response to glycine / propylene metabolic process / regulation of monoatomic cation transmembrane transport / Assembly and cell surface presentation of NMDA receptors / NMDA glutamate receptor activity / neurotransmitter receptor complex / NMDA selective glutamate receptor complex / Neurexins and neuroligins / ligand-gated sodium channel activity / glutamate binding / glutamate receptor signaling pathway / calcium ion transmembrane import into cytosol / protein heterotetramerization / glycine binding / startle response / positive regulation of reactive oxygen species biosynthetic process / monoatomic cation transmembrane transport / Negative regulation of NMDA receptor-mediated neuronal transmission / dopamine metabolic process / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of calcium ion transport into cytosol / Long-term potentiation / monoatomic cation transport / excitatory synapse / regulation of neuronal synaptic plasticity / monoatomic ion channel complex / positive regulation of excitatory postsynaptic potential / synaptic cleft / calcium ion homeostasis / MECP2 regulates neuronal receptors and channels / glutamate-gated calcium ion channel activity / neurogenesis / EPHB-mediated forward signaling / sensory perception of pain / sodium ion transmembrane transport / response to amphetamine / ionotropic glutamate receptor signaling pathway / positive regulation of synaptic transmission, glutamatergic / Ras activation upon Ca2+ influx through NMDA receptor / cytoplasmic vesicle membrane / excitatory postsynaptic potential / regulation of membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / synaptic membrane / protein catabolic process / postsynaptic density membrane / negative regulation of protein catabolic process / brain development / calcium ion transmembrane transport / visual learning / regulation of synaptic plasticity / response to wounding / long-term synaptic potentiation / memory / terminal bouton / synaptic vesicle / signaling receptor activity / amyloid-beta binding / presynaptic membrane / RAF/MAP kinase cascade / response to ethanol / chemical synaptic transmission / dendritic spine / postsynaptic membrane / learning or memory / neuron projection / calmodulin binding / postsynaptic density / positive regulation of apoptotic process / response to xenobiotic stimulus / synapse / dendrite / calcium ion binding / endoplasmic reticulum membrane / protein-containing complex binding / glutamatergic synapse / cell surface / positive regulation of transcription by RNA polymerase II / zinc ion binding / plasma membrane / cytoplasm
Similarity search - Function
Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / : / : / 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 / : ...Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / : / : / 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-7H0 / ACETATE ION / GLUTAMIC ACID / GLYCINE / Glutamate receptor ionotropic, NMDA 1 / Glutamate receptor ionotropic, NMDA 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsWallweber, H.J.A. / Lupardus, P.J.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved in Vivo Profile.
Authors: Villemure, E. / Volgraf, M. / Jiang, Y. / Wu, G. / Ly, C.Q. / Yuen, P.W. / Lu, A. / Luo, X. / Liu, M. / Zhang, S. / Lupardus, P.J. / Wallweber, H.J. / Liederer, B.M. / Deshmukh, G. / Plise, ...Authors: Villemure, E. / Volgraf, M. / Jiang, Y. / Wu, G. / Ly, C.Q. / Yuen, P.W. / Lu, A. / Luo, X. / Liu, M. / Zhang, S. / Lupardus, P.J. / Wallweber, H.J. / Liederer, B.M. / Deshmukh, G. / Plise, E. / Tay, S. / Wang, T.M. / Hanson, J.E. / Hackos, D.H. / Scearce-Levie, K. / Schwarz, J.B. / Sellers, B.D.
History
DepositionOct 20, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 30, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2016Group: Database references
Revision 1.2Feb 8, 2017Group: Database references
Revision 1.3Oct 16, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glutamate receptor ionotropic, NMDA 2A
B: Glutamate receptor ionotropic, NMDA 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0347
Polymers65,2932
Non-polymers7415
Water2,234124
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2450 Å2
ΔGint-11 kcal/mol
Surface area25180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.260, 89.780, 120.860
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Glutamate receptor ionotropic, NMDA ... , 2 types, 2 molecules AB

#1: Protein Glutamate receptor ionotropic, NMDA 2A / GluN2A / Glutamate [NMDA] receptor subunit epsilon-1 / N-methyl D-aspartate receptor subtype 2A / hNR2A


Mass: 31883.441 Da / Num. of mol.: 1
Fragment: Ligand binding domain (UNP residues 401-539, GT linker, UNP residues 661-802)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRIN2A, NMDAR2A / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q12879
#2: Protein Glutamate receptor ionotropic, NMDA 1 / GluN1 / Glutamate [NMDA] receptor subunit zeta-1 / N-methyl-D-aspartate receptor subunit NR1 / NMD-R1


Mass: 33409.074 Da / Num. of mol.: 1
Fragment: UNP residues 394-544, GT linker, UNP residues 663-800
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRIN1, NMDAR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q05586

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Non-polymers , 6 types, 129 molecules

#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C2H3O2
#4: Chemical ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H9NO4
#5: Chemical ChemComp-7H0 / 7-{[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide


Mass: 419.809 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H13ClF3N5O2S
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: Ca
#7: Chemical ChemComp-GLY / GLYCINE


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H5NO2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 124 / 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: 2.34 Å3/Da / Density % sol: 47.38 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.1 M HEPES, pH 7.0, 10-13% PEG8000, 2 mM calcium acetate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 15, 2014
RadiationMonochromator: liquid nitrogen-cooled dual crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 24941 / % possible obs: 100 % / Redundancy: 5.9 % / Biso Wilson estimate: 55.22 Å2 / Rmerge(I) obs: 0.081 / Net I/σ(I): 19.1
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 6.1 % / Rmerge(I) obs: 0.722 / Mean I/σ(I) obs: 2.7 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→47.67 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.93 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.377 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.392 / SU Rfree Blow DPI: 0.241 / SU Rfree Cruickshank DPI: 0.242
RfactorNum. reflection% reflectionSelection details
Rfree0.237 1251 5.03 %RANDOM
Rwork0.19 ---
obs0.192 24871 99.7 %-
Displacement parametersBiso mean: 53.11 Å2
Baniso -1Baniso -2Baniso -3
1--2.6684 Å20 Å20 Å2
2--4.0542 Å20 Å2
3----1.3858 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: 1 / Resolution: 2.4→47.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4382 0 32 124 4538
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014546HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.086161HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1579SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes107HARMONIC2
X-RAY DIFFRACTIONt_gen_planes686HARMONIC5
X-RAY DIFFRACTIONt_it4546HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.11
X-RAY DIFFRACTIONt_other_torsion18.28
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion596SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5142SEMIHARMONIC4
LS refinement shellResolution: 2.39→2.5 Å / Rfactor Rfree error: 0 / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.326 120 4.12 %
Rwork0.228 2794 -
all0.232 2914 -
obs--97.81 %

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