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

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Basic information

Entry
Database: PDB / ID: 6usu
TitleCrystal structure of GluN1/GluN2A ligand-binding domain in complex with L689,560 and glutamate
Components
  • Glutamate receptor ionotropic, NMDA 1
  • Glutamate receptor ionotropic, NMDA 2A
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 / directional locomotion / pons maturation / response to environmental enrichment / positive regulation of Schwann cell migration / 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 / directional locomotion / pons maturation / response to environmental enrichment / positive regulation of Schwann cell migration / regulation of cell communication / EPHB-mediated forward signaling / auditory behavior / Assembly and cell surface presentation of NMDA receptors / serotonin metabolic process / olfactory learning / conditioned taste aversion / response to hydrogen sulfide / dendritic branch / regulation of respiratory gaseous exchange / positive regulation of inhibitory postsynaptic potential / response to other organism / protein localization to postsynaptic membrane / cellular response to magnesium ion / regulation of ARF protein signal transduction / response to methylmercury / conditioned place preference / locomotion / dendritic spine organization / response to glycine / propylene metabolic process / response to carbohydrate / sleep / regulation of NMDA receptor activity / cellular response to dsRNA / cellular response to lipid / voltage-gated monoatomic cation channel activity / Synaptic adhesion-like molecules / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / RAF/MAP kinase cascade / response to manganese ion / transmitter-gated monoatomic ion channel activity / NMDA selective glutamate receptor complex / cellular response to zinc ion / ligand-gated sodium channel activity / response to morphine / glutamate receptor signaling pathway / calcium ion transmembrane import into cytosol / glutamate binding / regulation of axonogenesis / neuromuscular process / protein heterotetramerization / male mating behavior / regulation of dendrite morphogenesis / regulation of synapse assembly / spinal cord development / glycine binding / positive regulation of reactive oxygen species biosynthetic process / positive regulation of calcium ion transport into cytosol / parallel fiber to Purkinje cell synapse / suckling behavior / response to amine / startle response / dopamine metabolic process / social behavior / modulation of excitatory postsynaptic potential / response to lithium ion / associative learning / monoatomic cation transmembrane transport / regulation of neuronal synaptic plasticity / monoatomic cation transport / response to light stimulus / cellular response to glycine / positive regulation of excitatory postsynaptic potential / excitatory synapse / ligand-gated monoatomic ion channel activity / action potential / positive regulation of protein targeting to membrane / regulation of postsynaptic membrane potential / positive regulation of dendritic spine maintenance / Unblocking of NMDA receptors, glutamate binding and activation / long-term memory / cellular response to manganese ion / postsynaptic density, intracellular component / glutamate receptor binding / phosphatase binding / neuron development / multicellular organismal response to stress / synaptic cleft / prepulse inhibition / monoatomic cation channel activity / calcium ion homeostasis / glutamate-gated receptor activity / response to fungicide / cell adhesion molecule binding / presynaptic active zone membrane / regulation of neuron apoptotic process / dendrite membrane / glutamate-gated calcium ion channel activity / sensory perception of pain / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential
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
GLUTAMIC ACID / Chem-QGM / 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: 2.092 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 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

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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)65,6534
Polymers65,1252
Non-polymers5272
Water4,486249
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2360 Å2
ΔGint-4 kcal/mol
Surface area25240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.040, 87.341, 136.987
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#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
#3: Chemical ChemComp-QGM / (2R,4S)-5,7-dichloro-4-[(phenylcarbamoyl)amino]-1,2,3,4-tetrahydroquinoline-2-carboxylic acid


Mass: 380.225 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15Cl2N3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H9NO4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 249 / Source method: isolated from a natural source / Formula: H2O
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: 2.48 Å3/Da / Density % sol: 50.44 %
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: 1.1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 6, 2013
RadiationMonochromator: Double crystal cryo-cooled Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.09→40 Å / Num. obs: 38873 / % possible obs: 99.9 % / Redundancy: 7.6 % / Biso Wilson estimate: 25.56 Å2 / Rmerge(I) obs: 0.117 / Net I/σ(I): 17.1
Reflection shellResolution: 2.09→2.18 Å / Redundancy: 6 % / Rmerge(I) obs: 0.62 / Num. unique obs: 3781 / CC1/2: 0.814 / % possible all: 99.8

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.13_2998refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4NF8

4nf8


Resolution: 2.092→38.161 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 21.77
RfactorNum. reflection% reflection
Rfree0.2221 1881 4.87 %
Rwork0.1894 --
obs0.191 38642 98.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 77.3 Å2 / Biso mean: 27.2215 Å2 / Biso min: 12.93 Å2
Refinement stepCycle: final / Resolution: 2.092→38.161 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4337 0 35 249 4621
Biso mean--22.63 29.27 -
Num. residues----552
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.092-2.14850.28361150.223241786
2.1485-2.21170.26611570.218275899
2.2117-2.2830.27191310.20482855100
2.283-2.36460.25611650.20632798100
2.3646-2.45930.26271530.20452827100
2.4593-2.57120.25991520.20992834100
2.5712-2.70670.23581490.20162829100
2.7067-2.87630.23851380.2032823100
2.8763-3.09820.23491260.20962874100
3.0982-3.40990.22371340.2022889100
3.4099-3.90280.1941580.17262874100
3.9028-4.91550.18911430.14842940100
4.9155-38.1610.18951600.18473043100

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