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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


response to ammonium ion / directional locomotion / pons maturation / regulation of cell communication / positive regulation of Schwann cell migration / serotonin metabolic process / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / olfactory learning / conditioned taste aversion ...response to ammonium ion / directional locomotion / pons maturation / regulation of cell communication / positive regulation of Schwann cell migration / serotonin metabolic process / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / olfactory learning / conditioned taste aversion / protein localization to postsynaptic membrane / dendritic branch / regulation of respiratory gaseous exchange / propylene metabolic process / response to glycine / response to other organism / sleep / cellular response to magnesium ion / response to methylmercury / voltage-gated monoatomic cation channel activity / locomotion / response to morphine / glutamate-gated calcium ion channel activity / cellular response to dsRNA / response to carbohydrate / dendritic spine organization / regulation of monoatomic cation transmembrane transport / cellular response to lipid / NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / RAF/MAP kinase cascade / Synaptic adhesion-like molecules / parallel fiber to Purkinje cell synapse / calcium ion transmembrane import into cytosol / response to manganese ion / protein heterotetramerization / glutamate binding / positive regulation of reactive oxygen species biosynthetic process / cellular response to zinc ion / neuromuscular process / regulation of synapse assembly / action potential / glycine binding / positive regulation of calcium ion transport into cytosol / male mating behavior / regulation of neuronal synaptic plasticity / regulation of dendrite morphogenesis / dopamine metabolic process / regulation of axonogenesis / spinal cord development / suckling behavior / startle response / response to amine / monoatomic cation transmembrane transport / regulation of NMDA receptor activity / social behavior / positive regulation of excitatory postsynaptic potential / ligand-gated monoatomic ion channel activity / associative learning / monoatomic cation transport / excitatory synapse / response to light stimulus / positive regulation of dendritic spine maintenance / neuron development / Unblocking of NMDA receptors, glutamate binding and activation / long-term memory / glutamate receptor binding / regulation of postsynaptic membrane potential / phosphatase binding / calcium ion homeostasis / synaptic cleft / cellular response to manganese ion / prepulse inhibition / regulation of neuron apoptotic process / glutamate-gated receptor activity / presynaptic active zone membrane / response to fungicide / monoatomic cation channel activity / sensory perception of pain / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / response to amphetamine / excitatory postsynaptic potential / hippocampal mossy fiber to CA3 synapse / ionotropic glutamate receptor signaling pathway / regulation of membrane potential / cell adhesion molecule binding / neurogenesis / positive regulation of synaptic transmission, glutamatergic / adult locomotory behavior / response to cocaine / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic membrane / learning / synaptic transmission, glutamatergic / long-term synaptic potentiation / hippocampus development / cellular response to amino acid stimulus / postsynaptic density membrane / regulation of long-term neuronal synaptic plasticity
Similarity search - Function
Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site ...Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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 / 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 / Glycerol


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

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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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