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- EMDB-39582: Cryo-EM structure of the amthamine-bound H2R-Gs complex -

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Basic information

Entry
Database: EMDB / ID: EMD-39582
TitleCryo-EM structure of the amthamine-bound H2R-Gs complex
Map dataSharpened Map
Sample
  • Complex: amthamine-bound H2R-Gs complex
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody-35
    • Protein or peptide: Histamine H2 receptor
  • Ligand: 5-(2-azanylethyl)-4-methyl-1,3-thiazol-2-amine
  • Ligand: CHOLESTEROL
KeywordsGPCR / H2R / Histamine Receptor / MEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


gastric acid secretion / Histamine receptors / histamine receptor activity / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of vasoconstriction / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors ...gastric acid secretion / Histamine receptors / histamine receptor activity / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of vasoconstriction / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / chemical synaptic transmission / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / immune response / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / dendrite / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Histamine H2 receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit ...Histamine H2 receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Histamine H2 receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsShen Q / Tang X / Wen X / Cheng S / Xiao P / Zang S / Shen D / Jiang L / Zheng Y / Zhang H ...Shen Q / Tang X / Wen X / Cheng S / Xiao P / Zang S / Shen D / Jiang L / Zheng Y / Zhang H / Xu H / Mao C / Zhang M / Hu W / Sun J / Chen Z / Zhang Y
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2019YFA050880 China
CitationJournal: Adv Sci (Weinh) / Year: 2024
Title: Molecular Determinant Underlying Selective Coupling of Primary G-Protein by Class A GPCRs.
Authors: Qingya Shen / Xinyan Tang / Xin Wen / Shizhuo Cheng / Peng Xiao / Shao-Kun Zang / Dan-Dan Shen / Lei Jiang / Yanrong Zheng / Huibing Zhang / Haomang Xu / Chunyou Mao / Min Zhang / Weiwei Hu ...Authors: Qingya Shen / Xinyan Tang / Xin Wen / Shizhuo Cheng / Peng Xiao / Shao-Kun Zang / Dan-Dan Shen / Lei Jiang / Yanrong Zheng / Huibing Zhang / Haomang Xu / Chunyou Mao / Min Zhang / Weiwei Hu / Jin-Peng Sun / Yan Zhang / Zhong Chen /
Abstract: G-protein-coupled receptors (GPCRs) transmit downstream signals predominantly via G-protein pathways. However, the conformational basis of selective coupling of primary G-protein remains elusive. ...G-protein-coupled receptors (GPCRs) transmit downstream signals predominantly via G-protein pathways. However, the conformational basis of selective coupling of primary G-protein remains elusive. Histamine receptors HR and HR couple with G- or G-proteins respectively. Here, three cryo-EM structures of HR-G and HR-G complexes are presented at a global resolution of 2.6-2.7 Å. These structures reveal the unique binding pose for endogenous histamine in HR, wherein the amino group interacts with E206 of HR instead of the conserved D114 of other aminergic receptors. Furthermore, comparative analysis of the HR-G and HR-G complexes reveals that the structural geometry of TM5/TM6 determines the primary G-protein selectivity in histamine receptors. Machine learning (ML)-based structuromic profiling and functional analysis of class A GPCR-G-protein complexes illustrate that TM5 length, TM5 tilt, and TM6 outward movement are key determinants of the G and G selectivity among the whole Class A family. Collectively, the findings uncover the common structural geometry within class A GPCRs that determines the primary G- and G-coupling selectivity.
History
DepositionMar 27, 2024-
Header (metadata) releaseJun 5, 2024-
Map releaseJun 5, 2024-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_39582.png

Downloads & links

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Map

FileDownload / File: emd_39582.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened Map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 192 pix.
= 194.688 Å		1.01 Å/pix.
x 192 pix.
= 194.688 Å		1.01 Å/pix.
x 192 pix.
= 194.688 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.014 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.054
Minimum - Maximum-0.5977811 - 0.87880236
Average (Standard dev.)-0.00020881432 (±0.019771015)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 194.68802 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map 1

Fileemd_39582_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map2

Fileemd_39582_half_map_2.map
Annotationhalf map2
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : amthamine-bound H2R-Gs complex

EntireName: amthamine-bound H2R-Gs complex
Components
  • Complex: amthamine-bound H2R-Gs complex
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody-35
    • Protein or peptide: Histamine H2 receptor
  • Ligand: 5-(2-azanylethyl)-4-methyl-1,3-thiazol-2-amine
  • Ligand: CHOLESTEROL

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Supramolecule #1: amthamine-bound H2R-Gs complex

SupramoleculeName: amthamine-bound H2R-Gs complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.883762 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGYSE EECKQYKAVV YSNTIQSII AIIRAMGRLK IDFGDSARAD DARQLFVLAG AAEEGFMTAE LAGVIKRLWK DSGVQACFNR SREYQLNDSA A YYLNDLDR ...String:
MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGYSE EECKQYKAVV YSNTIQSII AIIRAMGRLK IDFGDSARAD DARQLFVLAG AAEEGFMTAE LAGVIKRLWK DSGVQACFNR SREYQLNDSA A YYLNDLDR IAQPNYIPTQ QDVLRTRVKT SGIFETKFQV DKVNFHMFDV GAQRDERRKW IQCFNDVTAI IFVVASSSYN MV IREDNQT NRLQEALNLF KSIWNNRWLR TISVILFLNK QDLLAEKVLA GKSKIEDYFP EFARYTTPED ATPEPGEDPR VTR AKYFIR DEFLRISTAS GDGRHYCYPH FTCSVDTENI RRVFNDCRDI IQRMHLRQYE LL

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.141793 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHLEVLF QGPGSSGSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSA SQDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT G YLSCCRFL ...String:
MHHHHLEVLF QGPGSSGSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSA SQDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT G YLSCCRFL DDNQIVTSSG DTTCALWDIE TGQQTTTFTG HTGDVMSLSL APDTRLFVSG ACDASAKLWD VREGMCRQTF TG HESDINA ICFFPNGNAF ATGSDDATCR LFDLRADQEL MTYSHDNIIC GITSVSFSKS GRLLLAGYDD FNCNVWDALK ADR AGVLAG HDNRVSCLGV TDDGMAVATG SWDSFLKIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: Nanobody-35

MacromoleculeName: Nanobody-35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 13.885439 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSS

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Macromolecule #5: Histamine H2 receptor

MacromoleculeName: Histamine H2 receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.456023 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKEFLEVL FQGPAPNGTA SSFCLDSTAC KITITVVLAV LILITVAGNV VVCLAVGLNR RLRNLTNCF IVSLAITDLL LGLLVLPFSA IYQLSCKWSF GKVFCNIYTS LDVMLCTASI LNLFMISLDR YCAVMDPLRY P VLVTPVRV ...String:
MKTIIALSYI FCLVFADYKD DDDKEFLEVL FQGPAPNGTA SSFCLDSTAC KITITVVLAV LILITVAGNV VVCLAVGLNR RLRNLTNCF IVSLAITDLL LGLLVLPFSA IYQLSCKWSF GKVFCNIYTS LDVMLCTASI LNLFMISLDR YCAVMDPLRY P VLVTPVRV AISLVLIWVI SITLSFLSIH LGWNSRNETS KGNHTTSKCK VQVNEVYGLV DGLVTFYLPL LIMCITYYRI FK VARDQAK RINHISSWKA ATIREHKATV TLAAVMGAFI ICWFPYFTAF VYRGLRGDDA INEVLEAIVL WLGYANSALN PIL YAALNR DFRTGYQQLF CCRLANRNSH KTSLRSNASQ LSRTQSREPR QQEEKPLKLQ VWSGTEVTAP QGATDRLEEN LYFQ GHHHH HHHHHH

UniProtKB: Histamine H2 receptor

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Macromolecule #6: 5-(2-azanylethyl)-4-methyl-1,3-thiazol-2-amine

MacromoleculeName: 5-(2-azanylethyl)-4-methyl-1,3-thiazol-2-amine / type: ligand / ID: 6 / Number of copies: 1 / Formula: A1D67
Molecular weightTheoretical: 157.237 Da

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Macromolecule #7: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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 / 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: 62.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 368447
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8yut:
Cryo-EM structure of the amthamine-bound H2R-Gs complex

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