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- EMDB-22117: Structure of human SMO-D384R complex with Gi -

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Basic information

Entry
Database: EMDB / ID: EMD-22117
TitleStructure of human SMO-D384R complex with Gi
Map data
SampleSMO-GI COMPLEX
  • Smoothened homolog
  • (Guanine nucleotide-binding protein ...) x 3
  • scFv16
  • ligand
Function / homology
Function and homology information


ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / smoothened signaling pathway involved in ventral spinal cord patterning / regulation of heart morphogenesis / cerebellar cortex morphogenesis / central nervous system neuron differentiation / epithelial-mesenchymal cell signaling / negative regulation of hair follicle development / forebrain morphogenesis / positive regulation of hh target transcription factor activity ...ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / smoothened signaling pathway involved in ventral spinal cord patterning / regulation of heart morphogenesis / cerebellar cortex morphogenesis / central nervous system neuron differentiation / epithelial-mesenchymal cell signaling / negative regulation of hair follicle development / forebrain morphogenesis / positive regulation of hh target transcription factor activity / determination of left/right asymmetry in lateral mesoderm / atrial septum morphogenesis / smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation / myoblast migration / contact inhibition / regulation of stem cell population maintenance / negative regulation of epithelial cell differentiation / dentate gyrus development / left/right axis specification / ciliary tip / dorsal/ventral neural tube patterning / somite development / patched binding / positive regulation of branching involved in ureteric bud morphogenesis / positive regulation of organ growth / cellular response to cholesterol / smooth muscle tissue development / type B pancreatic cell development / G protein-coupled serotonin receptor binding / positive regulation of protein localization to cell cortex / thalamus development / mammary gland epithelial cell differentiation / positive regulation of multicellular organism growth / cell cortex region / commissural neuron axon guidance / pancreas morphogenesis / positive regulation of smoothened signaling pathway / regulation of cAMP-mediated signaling / cardiac muscle cell apoptotic process / sensory perception of taste / smoothened signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein beta/gamma-subunit complex / cellular response to catecholamine stimulus / G-protein gamma-subunit binding / ciliary membrane / alkylglycerophosphoethanolamine phosphodiesterase activity / neural crest cell migration / rhodopsin mediated signaling pathway / regulation of mitotic spindle organization / adenylate cyclase-activating dopamine receptor signaling pathway / anterior/posterior pattern specification / photoreceptor outer segment membrane / G-protein beta-subunit binding / negative regulation of synaptic transmission / cellular response to forskolin / photoreceptor disc membrane / spectrin binding / cell fate specification / G-protein beta/gamma-subunit complex binding / heart looping / midgut development / positive regulation of mesenchymal cell proliferation / positive regulation of neuroblast proliferation / hair follicle morphogenesis / heterotrimeric G-protein complex / GTPase activating protein binding / protein localization to nucleus / skeletal muscle fiber development / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / extracellular vesicle / G protein-coupled receptor activity / Wnt signaling pathway, calcium modulating pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / cellular response to prostaglandin E stimulus / homeostasis of number of cells within a tissue / negative regulation of DNA binding / phospholipase C-activating G protein-coupled receptor signaling pathway / vasculogenesis / response to peptide hormone / GTPase binding / cilium / G protein-coupled receptor binding / central nervous system development / retina development in camera-type eye / astrocyte activation / osteoblast differentiation / photoreceptor inner segment / positive regulation of epithelial cell proliferation / cerebral cortex development / GDP binding / endocytic vesicle membrane / positive regulation of protein import into nucleus / odontogenesis of dentin-containing tooth / cell population proliferation / multicellular organism growth / cell body / midbody / lysosomal membrane / positive regulation of cytosolic calcium ion concentration
WD40-repeat-containing domain / Guanine nucleotide binding protein (G-protein), alpha subunit / WD40 repeat, conserved site / G-protein beta WD-40 repeat / Frizzled domain / Smoothened / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / Frizzled cysteine-rich domain superfamily / Smoothened, cysteine-rich domain ...WD40-repeat-containing domain / Guanine nucleotide binding protein (G-protein), alpha subunit / WD40 repeat, conserved site / G-protein beta WD-40 repeat / Frizzled domain / Smoothened / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / Frizzled cysteine-rich domain superfamily / Smoothened, cysteine-rich domain / Frizzled/Smoothened, transmembrane domain / P-loop containing nucleoside triphosphate hydrolase / G protein alpha subunit, helical insertion / GPCR, family 2-like / G-protein alpha subunit, group I / G-protein, beta subunit / WD40/YVTN repeat-like-containing domain superfamily / Guanine nucleotide-binding protein, beta subunit / WD40 repeat / G-protein, gamma subunit / G-protein gamma-like domain / Frizzled/secreted frizzled-related protein
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 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Smoothened homolog
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.88 Å
AuthorsQi X / Long T / Li X
CitationJournal: Nat Chem Biol / Year: 2020
Title: Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling.
Authors: Xiaofeng Qi / Lucas Friedberg / Ryan De Bose-Boyd / Tao Long / Xiaochun Li /
Abstract: Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain ...Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain (CRD) and to several sites in the seven transmembrane helices (7-TMs) of SMO. However, the mechanism by which sterols regulate SMO via multiple sites is unknown. Here we determined the structures of SMO-G complexes bound to the synthetic SMO agonist (SAG) and to 24(S),25-epoxycholesterol (24(S),25-EC). A novel sterol-binding site in the extracellular extension of TM6 was revealed to connect other sites in 7-TMs and CRD, forming an intramolecular sterol channel from the middle side of 7-TMs to CRD. Additional structures of two gain-of-function variants, SMO and SMO, showed that blocking the channel at its midpoints allows sterols to occupy the binding sites in 7-TMs, thereby activating SMO. These data indicate that sterol transport through the core of SMO is a major regulator of SMO-mediated signaling.
Validation ReportPDB-ID: 6xbj

SummaryFull reportAbout validation report
History
DepositionJun 6, 2020-
Header (metadata) releaseSep 30, 2020-
Map releaseSep 30, 2020-
UpdateNov 25, 2020-
Current statusNov 25, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.013
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6xbj
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_22117.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 280 pix.
= 233.24 Å
0.83 Å/pix.
x 280 pix.
= 233.24 Å
0.83 Å/pix.
x 280 pix.
= 233.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.833 Å
Density
Contour LevelBy AUTHOR: 0.01 / Movie #1: 0.013
Minimum - Maximum-0.057521917 - 0.09059946
Average (Standard dev.)0.00002165496 (±0.0022909842)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 233.24 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8330.8330.833
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z233.240233.240233.240
α/β/γ90.00090.00090.000
start NX/NY/NZ212211153
NX/NY/NZ80102186
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-0.0580.0910.000

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Supplemental data

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Segmentation: #1

Fileemd_22117_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: half-volume 1

Fileemd_22117_half_map_1.map
Annotationhalf-volume 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: half-volume 2

Fileemd_22117_half_map_2.map
Annotationhalf-volume 2
Projections & Slices
AxesZYX

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Slices (1/2)
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Sample components

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Entire SMO-GI COMPLEX

EntireName: SMO-GI COMPLEX / Number of components: 7

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Component #1: protein, SMO-GI COMPLEX

ProteinName: SMO-GI COMPLEX / Recombinant expression: No
SourceSpecies: Homo sapiens (human)

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Component #2: protein, Smoothened homolog

ProteinName: Smoothened homolog / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 71.828547 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, Guanine nucleotide-binding protein G(i) subunit alpha-1

ProteinName: Guanine nucleotide-binding protein G(i) subunit alpha-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 40.415031 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #4: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 37.671102 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #5: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 7.861143 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #6: protein, scFv16

ProteinName: scFv16 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 27.784896 kDa
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #7: ligand, CHOLESTEROL

LigandName: CHOLESTEROL / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.386654 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 60 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: DARK FIELD
Specimen HolderModel: OTHER
CameraDetector: OTHER

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 621773
3D reconstructionResolution: 3.88 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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