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- EMDB-21679: GluN1b-GluN2B NMDA receptor in complex with GluN2B antagonist SDZ... -

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Basic information

Entry
Database: EMDB / ID: EMD-21679
TitleGluN1b-GluN2B NMDA receptor in complex with GluN2B antagonist SDZ 220-040, class 2
Map dataB factor sharpened (-90)
Sample
  • Complex: NMDA receptor GluN1b/2B functional ion channel complex
    • Protein or peptide: Ionotropic glutamate receptor , NMDA receptor GluN1b
    • Protein or peptide: Ionotropic glutamate receptor , NMDA receptor GluN2B
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2S)-2-amino-3-[2',4'-dichloro-4-hydroxy-5-(phosphonomethyl)biphenyl-3-yl]propanoic acid
KeywordsNMDARs / Ligand-gated ion channels / METAL TRANSPORT / Ionotropic glutamate receptor / MEMBRANE PROTEIN / GluN2B antagonist
Function / homology
Function and homology information


neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / cellular response to curcumin / cellular response to corticosterone stimulus / regulation of postsynaptic cytosolic calcium ion concentration / cellular response to magnesium starvation / sensory organ development / sensitization / pons maturation / positive regulation of Schwann cell migration / regulation of cell communication ...neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / cellular response to curcumin / cellular response to corticosterone stimulus / regulation of postsynaptic cytosolic calcium ion concentration / cellular response to magnesium starvation / sensory organ development / sensitization / pons maturation / positive regulation of Schwann cell migration / regulation of cell communication / EPHB-mediated forward signaling / Assembly and cell surface presentation of NMDA receptors / olfactory learning / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / regulation of protein kinase A signaling / conditioned taste aversion / response to hydrogen sulfide / regulation of respiratory gaseous exchange / dendritic branch / positive regulation of inhibitory postsynaptic potential / apical dendrite / protein localization to postsynaptic membrane / regulation of ARF protein signal transduction / fear response / response to methylmercury / response to other organism / propylene metabolic process / response to glycine / positive regulation of cysteine-type endopeptidase activity / response to carbohydrate / negative regulation of dendritic spine maintenance / cellular response to dsRNA / interleukin-1 receptor binding / voltage-gated monoatomic cation channel activity / cellular response to lipid / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / response to growth hormone / positive regulation of glutamate secretion / Synaptic adhesion-like molecules / RAF/MAP kinase cascade / NMDA selective glutamate receptor complex / response to manganese ion / parallel fiber to Purkinje cell synapse / response to morphine / NMDA selective glutamate receptor signaling pathway / calcium ion transmembrane import into cytosol / glutamate binding / neuromuscular process / protein heterotetramerization / regulation of synapse assembly / positive regulation of reactive oxygen species biosynthetic process / male mating behavior / regulation of axonogenesis / regulation of dendrite morphogenesis / glycine binding / positive regulation of calcium ion transport into cytosol / heterocyclic compound binding / receptor clustering / suckling behavior / response to amine / startle response / small molecule binding / monoatomic cation transmembrane transport / action potential / regulation of neuronal synaptic plasticity / associative learning / monoatomic cation transport / behavioral response to pain / regulation of MAPK cascade / social behavior / response to magnesium ion / ligand-gated monoatomic ion channel activity / extracellularly glutamate-gated ion channel activity / positive regulation of excitatory postsynaptic potential / cellular response to organic cyclic compound / cellular response to glycine / excitatory synapse / positive regulation of dendritic spine maintenance / regulation of postsynaptic membrane potential / Unblocking of NMDA receptors, glutamate binding and activation / behavioral fear response / cellular response to manganese ion / postsynaptic density, intracellular component / phosphatase binding / glutamate receptor binding / neuron development / multicellular organismal response to stress / long-term memory / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / calcium ion homeostasis / monoatomic cation channel activity / D2 dopamine receptor binding / response to electrical stimulus / regulation of neuron apoptotic process / glutamate-gated receptor activity / synaptic cleft / response to fungicide / response to mechanical stimulus
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 I
Similarity search - Domain/homology
Glutamate receptor ionotropic, NMDA 1 / Glutamate receptor ionotropic, NMDA 2B
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.09 Å
AuthorsChou T / Tajima N
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)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
DepositionApr 8, 2020-
Header (metadata) releaseJul 15, 2020-
Map releaseJul 15, 2020-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 4.5
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 4.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6whx
  • Surface level: 4.5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21679.png

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Map

FileDownload / File: emd_21679.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationB factor sharpened (-90)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.37 Å/pix.
x 256 pix.
= 350.72 Å		1.37 Å/pix.
x 256 pix.
= 350.72 Å		1.37 Å/pix.
x 256 pix.
= 350.72 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.37 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.93 / Movie #1: 4.5
Minimum - Maximum-11.207095000000001 - 18.938559999999999
Average (Standard dev.)-0.019389331 (±1.0308149)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 350.72 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.371.371.37
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z350.720350.720350.720
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ512512512
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-11.20718.939-0.019

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Supplemental data

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Additional map: Unsharpened map

Fileemd_21679_additional.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : NMDA receptor GluN1b/2B functional ion channel complex

EntireName: NMDA receptor GluN1b/2B functional ion channel complex
Components
  • Complex: NMDA receptor GluN1b/2B functional ion channel complex
    • Protein or peptide: Ionotropic glutamate receptor , NMDA receptor GluN1b
    • Protein or peptide: Ionotropic glutamate receptor , NMDA receptor GluN2B
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2S)-2-amino-3-[2',4'-dichloro-4-hydroxy-5-(phosphonomethyl)biphenyl-3-yl]propanoic acid

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Supramolecule #1: NMDA receptor GluN1b/2B functional ion channel complex

SupramoleculeName: NMDA receptor GluN1b/2B functional ion channel complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Macromolecule #1: Ionotropic glutamate receptor , NMDA receptor GluN1b

MacromoleculeName: Ionotropic glutamate receptor , NMDA receptor GluN1b / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 108.085633 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSTMHLLTFA LLFSCSFARA ASDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL QATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYN W NHIILLVS ...String:
MSTMHLLTFA LLFSCSFARA ASDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL QATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYN W NHIILLVS DDHEGRAAQK RLETLLEERE SKSKKRNYEN LDQLSYDNKR GPKAEKVLQF DPGTKNVTAL LMEARELEAR VI ILSASED DAATVYRAAA MLDMTGSGYV WLVGEREISG NALRYAPDGI IGLQLINGKN ESAHISDAVG VVAQAVHELL EKE NITDPP RGCVGNTNIW KTGPLFKRVL MSSKYADGVT GRVEFNEDGD RKFAQYSIMN LQNRKLVQVG IYNGTHVIPN DRKI IWPGG ETEKPRGYQM STRLKIVTIH QEPFVYVKPT MSDGTCKEEF TVNGDPVKKV ICTGPNDTSP GSPRHTVPQC CYGFC IDLL IKLARTMQFT YEVHLVADGK FGTQERVQNS NKKEWNGMMG ELLSGQADMI VAPLTINNER AQYIEFSKPF KYQGLT ILV KKEIPRSTLD SFMQPFQSTL WLLVGLSVHV VAVMLYLLDR FSPFGRFKVN SQSESTDALT LSSAMWFSWG VLLNSGI GE GAPRSFSARI LGMVWAGFAM IIVASYTANL AAFLVLDRPE ERITGINDPR LRNPSDKFIY ATVKQSSVDI YFRRQVEL S TMYRHMEKHN YESAAEAIQA VRDNKLHAFI WDSAVLEFEA SQKCDLVTTG ELFFRSGFGI GMRKDSPWKQ QVSLSILKS HENGFMEDLD KTWVRYQECD SRSNAPATLT CENMAGVFML VAGGIVAGIF LIFIEIAYKR HKDARRKQMQ LAFAAVNVWR KNLQDRKSG RAEPDPKKKA TFRAITSTLA SSFKRRRSSK DTSTGGGRGA LQNQKDTVLP RRAIEREEGQ LQLCSRHRES

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Macromolecule #2: Ionotropic glutamate receptor , NMDA receptor GluN2B

MacromoleculeName: Ionotropic glutamate receptor , NMDA receptor GluN2B / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 98.845859 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGTMRLFLLA VLFLFSFARA TGWSHPQFEK GGGSGGGSGG SAWSHPQFEK GALVPRGRSQ KSPPSIGIAV ILVGTSDEVA IKDAHEKDD FHHLSVVPRV ELVAMNETDP KSIITRICDL MSDRKIQGVV FADDTDQEAI AQILDFISAQ TLTPILGIHG G SSMIMADK ...String:
MGTMRLFLLA VLFLFSFARA TGWSHPQFEK GGGSGGGSGG SAWSHPQFEK GALVPRGRSQ KSPPSIGIAV ILVGTSDEVA IKDAHEKDD FHHLSVVPRV ELVAMNETDP KSIITRICDL MSDRKIQGVV FADDTDQEAI AQILDFISAQ TLTPILGIHG G SSMIMADK DESSMFFQFG PSIEQQASVM LNIMEEYDWY IFSIVTTYFP GYQDFVNKIR STIENSFVGW ELEEVLLLDM SL DDGDSKI QNQLKKLQSP IILLYCTKEE ATYIFEVANS VGLTGYGYTW IVPSLVAGDT DTVPSEFPTG LISVSYDEWD YGL PARVRD GIAIITTAAS DMLSEHSFIP EPKSSCYNTH EKRIYQSNML NRYLINVTFE GRDLSFSEDG YQMHPKLVII LLNK ERKWE RVGKWKDKSL QMKYYVWPRM CPETEEQEDD HLSIVTLEEA PFVIVESVDP LSGTCMRNTV PCQKRIISEN KTDEE PGYI KKCCKGFCID ILKKISKSVK FTYDLYLVTN GKHGKKINGT WNGMIGEVVM KRAYMAVGSL TINEERSEVV DFSVPF IET GISVMVSRSN GTVSPSAFLE PFSACVWVMM FVMLLIVSAV AVFVFEYFSP VGYNRSLADG REPGGPSFTI GKAIWLL WG LVFNNSVPVQ NPKGTTSKIM VSVWAFFAVI FLASYTANLA AFMIQEEYVD QVSGLSDKKF QRPNDFSPPF RFGTVPNG S TERNIRNNYA EMHAYMGKFN QRGVDDALLS LKTGKLDAFI YDAAVLNYMA GRDEGCKLVT IGSGKVFAST GYGIAIQKD SGWKRQVDLA ILQLFGDGEM EELEALWLTG ICHNEKNEVM SSQLDIDNMA GVFYMLGAAM ALSLITFISE HLFYWQFRHS FMG

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #4: (2S)-2-amino-3-[2',4'-dichloro-4-hydroxy-5-(phosphonomethyl)biphe...

MacromoleculeName: (2S)-2-amino-3-[2',4'-dichloro-4-hydroxy-5-(phosphonomethyl)biphenyl-3-yl]propanoic acid
type: ligand / ID: 4 / Number of copies: 2 / Formula: QGP
Molecular weightTheoretical: 420.181 Da
Chemical component information

ChemComp-QGP:
(2S)-2-amino-3-[2',4'-dichloro-4-hydroxy-5-(phosphonomethyl)biphenyl-3-yl]propanoic acid

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 85 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 64.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Ab initio reconstruction
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.09 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cisTEM (ver. 1.0.0) / Number images used: 109232
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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