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- PDB-6usv: Crystal structure of GluN1/GluN2A ligand-binding domain in comple... -

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Basic information

Entry
Database: PDB / ID: 6usv
TitleCrystal structure of GluN1/GluN2A ligand-binding domain in complex with glycine and SDZ 220-040
Components(Glutamate receptor ionotropic, NMDA ...) x 2
KeywordsMETAL TRANSPORT / NMDARs / LBD / Ion channels
Function / homology
Function and homology information


neurotransmitter receptor transport, plasma membrane to endosome / regulation of response to alcohol / response to ammonium ion / receptor recycling / response to environmental enrichment / directional locomotion / positive regulation of Schwann cell migration / pons maturation / regulation of cell communication / EPHB-mediated forward signaling ...neurotransmitter receptor transport, plasma membrane to endosome / regulation of response to alcohol / response to ammonium ion / receptor recycling / response to environmental enrichment / directional locomotion / positive regulation of Schwann cell migration / pons maturation / regulation of cell communication / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / response to hydrogen sulfide / auditory behavior / olfactory learning / conditioned taste aversion / dendritic branch / regulation of respiratory gaseous exchange / regulation of ARF protein signal transduction / response to other organism / protein localization to postsynaptic membrane / cellular response to magnesium ion / serotonin metabolic process / transmitter-gated monoatomic ion channel activity / positive regulation of inhibitory postsynaptic potential / response to methylmercury / suckling behavior / response to manganese ion / response to glycine / response to carbohydrate / propylene metabolic process / sleep / dendritic spine organization / cellular response to dsRNA / locomotion / regulation of NMDA receptor activity / cellular response to lipid / RAF/MAP kinase cascade / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / response to amine / Synaptic adhesion-like molecules / response to glycoside / voltage-gated monoatomic cation channel activity / NMDA selective glutamate receptor complex / glutamate binding / neurotransmitter receptor complex / ligand-gated sodium channel activity / glutamate receptor signaling pathway / regulation of axonogenesis / calcium ion transmembrane import into cytosol / neuromuscular process / response to morphine / regulation of dendrite morphogenesis / protein heterotetramerization / male mating behavior / regulation of synapse assembly / glycine binding / spinal cord development / cellular response to zinc ion / startle response / positive regulation of reactive oxygen species biosynthetic process / dopamine metabolic process / parallel fiber to Purkinje cell synapse / response to lithium ion / monoatomic cation transmembrane transport / monoatomic ion channel complex / positive regulation of calcium ion transport into cytosol / regulation of postsynaptic membrane potential / cellular response to glycine / action potential / modulation of excitatory postsynaptic potential / response to light stimulus / associative learning / positive regulation of dendritic spine maintenance / regulation of neuronal synaptic plasticity / monoatomic cation transport / social behavior / conditioned place preference / positive regulation of protein targeting to membrane / glutamate receptor binding / Unblocking of NMDA receptors, glutamate binding and activation / prepulse inhibition / long-term memory / neuron development / phosphatase binding / multicellular organismal response to stress / positive regulation of synaptic transmission, glutamatergic / postsynaptic density, intracellular component / synaptic cleft / monoatomic cation channel activity / calcium ion homeostasis / response to fungicide / glutamate-gated receptor activity / cellular response to manganese ion / glutamate-gated calcium ion channel activity / presynaptic active zone membrane / neurogenesis / cell adhesion molecule binding / dendrite membrane / excitatory synapse
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 / D-Maltodextrin-Binding Protein; domain 2 / Periplasmic binding protein-like I / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
GLYCINE / Chem-QGP / Glutamate receptor ionotropic, NMDA 1 / Glutamate receptor ionotropic, NMDA 2A
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.304 Å
AuthorsRomero-Hernandez, A. / Tajima, N. / Chou, T. / Furukawa, h.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)NS111745 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)MH085926 United States
CitationJournal: Cell / Year: 2020
Title: Structural Basis of Functional Transitions in Mammalian NMDA Receptors.
Authors: Tsung-Han Chou / Nami Tajima / Annabel Romero-Hernandez / Hiro Furukawa /
Abstract: Excitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of ...Excitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of GluN1 and GluN2 subunits, which bind glycine and glutamate, respectively, to activate their ion channels. Despite importance in brain physiology, the precise mechanisms by which activation and inhibition occur via subunit-specific binding of agonists and antagonists remain largely unknown. Here, we show the detailed patterns of conformational changes and inter-subunit and -domain reorientation leading to agonist-gating and subunit-dependent competitive inhibition by providing multiple structures in distinct ligand states at 4 Å or better. The structures reveal that activation and competitive inhibition by both GluN1 and GluN2 antagonists occur by controlling the tension of the linker between the ligand-binding domain and the transmembrane ion channel of the GluN2 subunit. Our results provide detailed mechanistic insights into NMDAR pharmacology, activation, and inhibition, which are fundamental to the brain physiology.
History
DepositionOct 28, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 5, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.2Oct 11, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 9, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)65,7135
Polymers65,1252
Non-polymers5873
Water75742
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2610 Å2
ΔGint-4 kcal/mol
Surface area25660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.281, 85.131, 121.675
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 1 / GluN1 / Glutamate [NMDA] receptor subunit zeta-1 / N-methyl-D-aspartate receptor subunit NR1 / NMD-R1


Mass: 33340.031 Da / Num. of mol.: 1 / Fragment: UNP residues 415-565, 684-821
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Grin1, Nmdar1 / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: P35439
#2: Protein Glutamate receptor ionotropic, NMDA 2A / GluN2A / Glutamate [NMDA] receptor subunit epsilon-1 / N-methyl D-aspartate receptor subtype 2A / NR2A


Mass: 31785.299 Da / Num. of mol.: 1 / Fragment: UNP residues 402-539, 661-802
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Grin2a / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: Q00959

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Non-polymers , 4 types, 45 molecules

#3: Chemical ChemComp-GLY / GLYCINE


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H5NO2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-QGP / (2S)-2-amino-3-[2',4'-dichloro-4-hydroxy-5-(phosphonomethyl)biphenyl-3-yl]propanoic acid


Mass: 420.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16Cl2NO6P / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 42 / 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: 2.36 Å3/Da / Density % sol: 47.82 %
Crystal growTemperature: 291 K / Method: evaporation / pH: 7
Details: 0.2 M HEPES, pH 7.0, 60-90 mM sodium chloride, 15-20% PEG2000 MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 0.97 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 11, 2013
RadiationMonochromator: Double crystal cryo-cooled Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.3→49.5 Å / Num. obs: 26575 / % possible obs: 95 % / Redundancy: 4.8 % / Biso Wilson estimate: 44.07 Å2 / Rpim(I) all: 0.042 / Rsym value: 0.082 / Net I/σ(I): 9.5
Reflection shellResolution: 2.3→2.34 Å / Num. unique obs: 1276 / CC1/2: 0.872 / Rpim(I) all: 0.579

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.8.4_1496refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4NF8

4nf8


Resolution: 2.304→49.497 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 28.37
RfactorNum. reflection% reflection
Rfree0.2594 1338 5.04 %
Rwork0.1952 --
obs0.1984 26538 94.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 86.96 Å2 / Biso mean: 45.8 Å2 / Biso min: 22.81 Å2
Refinement stepCycle: final / Resolution: 2.304→49.497 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4366 0 37 42 4445
Biso mean--45.03 41.68 -
Num. residues----553
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084501
X-RAY DIFFRACTIONf_angle_d1.0846074
X-RAY DIFFRACTIONf_chiral_restr0.041674
X-RAY DIFFRACTIONf_plane_restr0.005774
X-RAY DIFFRACTIONf_dihedral_angle_d16.0631665
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.304-2.3860.32781450.2436238292
2.386-2.48160.34341230.2551244094
2.4816-2.59450.34441290.2554246494
2.5945-2.73130.35631220.2422241193
2.7313-2.90240.31371210.2465245293
2.9024-3.12650.3471220.2388247593
3.1265-3.4410.31390.2113247494
3.441-3.93880.21711380.1849260698
3.9388-4.96170.20561400.14872686100
4.9617-49.490.22611590.17422810100

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