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- EMDB-27329: Cryo-EM structure of cyanopindolol-bound beta1-adrenergic recepto... -

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Entry
Database: EMDB / ID: EMD-27329
TitleCryo-EM structure of cyanopindolol-bound beta1-adrenergic receptor in complex with heterotrimeric Gs-protein
Map datacomposite map
Sample
  • Complex: cyanopindolol-bound beta1-adrenergic receptor in complex with heterotrimeric Gs-protein
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Nanobody 35
    • 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(O) subunit gamma-2
    • Protein or peptide: Endolysin,Endolysin,Beta-1 adrenergic receptor chimera
  • Ligand: 4-{[(2S)-3-(tert-butylamino)-2-hydroxypropyl]oxy}-3H-indole-2-carbonitrile
Function / homology
Function and homology information


Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / sensory perception of chemical stimulus / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / Activation of the phototransduction cascade / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma ...Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / sensory perception of chemical stimulus / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / Activation of the phototransduction cascade / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / beta-2 adrenergic receptor binding / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / Extra-nuclear estrogen signaling / G alpha (z) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (i) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / D1 dopamine receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / viral release from host cell by cytolysis / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / adenylate cyclase activator activity / peptidoglycan catabolic process / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / photoreceptor disc membrane / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / cell wall macromolecule catabolic process / signaling receptor complex adaptor activity / lysozyme / lysozyme activity / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / host cell cytoplasm / defense response to bacterium / G protein-coupled receptor signaling pathway / GTPase activity / GTP binding / membrane / metal ion binding / plasma membrane / cytoplasm
Similarity search - Function
G-protein alpha subunit, group S / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit ...G-protein alpha subunit, group S / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / Lysozyme-like domain superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Endolysin / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesMeleagris gallopavo (turkey) / Bos taurus (cattle) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsSu M / Paknejad N / Hite RK / Huang XY
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM138676 United States
CitationJournal: Nat Commun / Year: 2022
Title: Structures of β-adrenergic receptor in complex with Gs and ligands of different efficacies.
Authors: Minfei Su / Navid Paknejad / Lan Zhu / Jinan Wang / Hung Nguyen Do / Yinglong Miao / Wei Liu / Richard K Hite / Xin-Yun Huang /
Abstract: G-protein-coupled receptors (GPCRs) receive signals from ligands with different efficacies, and transduce to heterotrimeric G-proteins to generate different degrees of physiological responses. ...G-protein-coupled receptors (GPCRs) receive signals from ligands with different efficacies, and transduce to heterotrimeric G-proteins to generate different degrees of physiological responses. Previous studies revealed how ligands with different efficacies activate GPCRs. Here, we investigate how a GPCR activates G-proteins upon binding ligands with different efficacies. We report the cryo-EM structures of β-adrenergic receptor (β-AR) in complex with Gs (GαGβGγ) and a partial agonist or a very weak partial agonist, and compare them to the β-AR-Gs structure in complex with a full agonist. Analyses reveal similar overall complex architecture, with local conformational differences. Cellular functional studies with mutations of β-AR residues show effects on the cellular signaling from β-AR to the cAMP response initiated by the three different ligands, with residue-specific functional differences. Biochemical investigations uncover that the intermediate state complex comprising β-AR and nucleotide-free Gs is more stable when binding a full agonist than a partial agonist. Molecular dynamics simulations support the local conformational flexibilities and different stabilities among the three complexes. These data provide insights into the ligand efficacy in the activation of GPCRs and G-proteins.
History
DepositionJun 17, 2022-
Header (metadata) releaseJul 27, 2022-
Map releaseJul 27, 2022-
UpdateJul 27, 2022-
Current statusJul 27, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27329.png

Downloads & links

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Map

FileDownload / File: emd_27329.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcomposite map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.71 Å/pix.
x 384 pix.
= 272.371 Å		0.71 Å/pix.
x 384 pix.
= 272.371 Å		0.71 Å/pix.
x 384 pix.
= 272.371 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.7093 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 3.0
Minimum - Maximum-45.06655 - 71.124756
Average (Standard dev.)0.00036807428 (±1.0401154)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 272.3712 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: consensus map

Fileemd_27329_additional_1.map
Annotationconsensus map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: G-protein focused map

Fileemd_27329_additional_2.map
AnnotationG-protein focused map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Additional map: Receptor focused map

Fileemd_27329_additional_3.map
AnnotationReceptor focused map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: consensus map-half A

Fileemd_27329_half_map_1.map
Annotationconsensus_map-half_A
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: consensus map-half B

Fileemd_27329_half_map_2.map
Annotationconsensus_map-half_B
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : cyanopindolol-bound beta1-adrenergic receptor in complex with het...

EntireName: cyanopindolol-bound beta1-adrenergic receptor in complex with heterotrimeric Gs-protein
Components
  • Complex: cyanopindolol-bound beta1-adrenergic receptor in complex with heterotrimeric Gs-protein
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Nanobody 35
    • 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(O) subunit gamma-2
    • Protein or peptide: Endolysin,Endolysin,Beta-1 adrenergic receptor chimera
  • Ligand: 4-{[(2S)-3-(tert-butylamino)-2-hydroxypropyl]oxy}-3H-indole-2-carbonitrile

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Supramolecule #1: cyanopindolol-bound beta1-adrenergic receptor in complex with het...

SupramoleculeName: cyanopindolol-bound beta1-adrenergic receptor in complex with heterotrimeric Gs-protein
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Meleagris gallopavo (turkey)

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Macromolecule #1: 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: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (cattle)
Molecular weightTheoretical: 37.285734 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW ...String:
SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NAICFFPNGN AF ATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGHDNRVSCL GVT DDGMAV ATGSWDSFLK IWN

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Macromolecule #2: Nanobody 35

MacromoleculeName: Nanobody 35 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 15.282897 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
AAQVQLQESG GGLVQPGGSL RLSCAASGFT FSNYKMNWVR QAPGKGLEWV SDISQSGASI SYTGSVKGRF TISRDNAKNT LYLQMNSLK PEDTAVYYCA RCPAPFTRDC FDVTSTTYAY RGQGTQVTVS SHHHHHHEPE A

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (cattle)
Molecular weightTheoretical: 44.694551 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GPLAMGCLGN SKTEDQRNEE KGQREANKKI EKQLQKDKQV YRATHRLLLL GAGESGKSTI VKQMRILHVN GFNGDSEKAT KVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV RACYERSNEY Q LIDCAQYF ...String:
GPLAMGCLGN SKTEDQRNEE KGQREANKKI EKQLQKDKQV YRATHRLLLL GAGESGKSTI VKQMRILHVN GFNGDSEKAT KVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV RACYERSNEY Q LIDCAQYF LDKIDVIKQD DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGGQR DERRKWIQCF NDVTAIIFVV AS SSYNMVI REDNQTNRLQ EALNLFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTTPEDATPE PGE DPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENIRRVF NDCRDIIQRM HLRQYELL

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Macromolecule #4: 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: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (cattle)
Molecular weightTheoretical: 7.845078 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFSAI L

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Macromolecule #5: Endolysin,Endolysin,Beta-1 adrenergic receptor chimera

MacromoleculeName: Endolysin,Endolysin,Beta-1 adrenergic receptor chimera
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO / EC number: lysozyme
Source (natural)Organism: Meleagris gallopavo (turkey)
Molecular weightTheoretical: 57.958668 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKLEVLFQ GPNIFEMLRI DEGLRLKIYK DTEGYYTIGI GHLLTKSPSL NAAKSELDKA IGRNTNGVI TKDEAEKLFN QDVDAAVRGI LRNAKLKPVY DSLDAVRRAA LINMVFQMGE TGVAGFTNSL RMLQQKRWDE A AVNLAKSR ...String:
MKTIIALSYI FCLVFADYKD DDDKLEVLFQ GPNIFEMLRI DEGLRLKIYK DTEGYYTIGI GHLLTKSPSL NAAKSELDKA IGRNTNGVI TKDEAEKLFN QDVDAAVRGI LRNAKLKPVY DSLDAVRRAA LINMVFQMGE TGVAGFTNSL RMLQQKRWDE A AVNLAKSR WYNQTPNRAK RVITTFRTGT WDAYAAGAEL LSQQWEAGMS LLMALVVLLI VAGNVLVIAA IGSTQRLQTL TN LFITSLA CADLVVGLLV VPFGATLVVR GTWLWGSFLC ELWTSLDVLC VTASIETLCV IAIDRYLAIT SPFRYQSLMT RAR AKVIIC TVWAISALVS FLPIMMHWWR DEDPQALKCY QDPGCCDFVT NRAYAIASSI ISFYIPLLIM IFVYLRVYRE AKEQ IRKID RCEGRFREHK ALKTLGIIMG VFTLCWLPFF LVNIVNVFNR DLVPDWLFVF FNWLGYANSA FNPIIYCRSP DFRKA FKRL LCFPRKADRR LEVLFQGPHH HHHH

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Macromolecule #6: 4-{[(2S)-3-(tert-butylamino)-2-hydroxypropyl]oxy}-3H-indole-2-car...

MacromoleculeName: 4-{[(2S)-3-(tert-butylamino)-2-hydroxypropyl]oxy}-3H-indole-2-carbonitrile
type: ligand / ID: 6 / Number of copies: 1 / Formula: P32
Molecular weightTheoretical: 287.357 Da
Chemical component information

ChemComp-P32:
4-{[(2S)-3-(tert-butylamino)-2-hydroxypropyl]oxy}-3H-indole-2-carbonitrile

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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

Concentration1.8 mg/mL
BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 28.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7jjo

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 657613
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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