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- EMDB-22120: Structure of human SMO-Gi complex with 24(S),25-EC -

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Basic information

Entry
Database: EMDB / ID: EMD-22120
TitleStructure of human SMO-Gi complex with 24(S),25-EC
Map dataStructure of human SMO-Gi complex with 24(S),25-EC
Sample
  • Complex: SMO-GI COMPLEX
    • Protein or peptide: Smoothened homolog
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • 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: scFv16
  • Ligand: 17-[3-(3,3-DIMETHYL-OXIRANYL)-1-METHYL-PROPYL]-10,13-DIMETHYL-2,3,4,7,8,9,10,11,12,13,14,15,16,17-TETRADECAHYDRO-1H-CYC LOPENTA[A]PHENANTHREN-3-OL
Function / homology
Function and homology information


ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / regulation of heart morphogenesis / negative regulation of hair follicle development / 9+0 non-motile cilium / central nervous system neuron differentiation / regulation of somatic stem cell population maintenance / pancreas morphogenesis / epithelial-mesenchymal cell signaling / : ...ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / regulation of heart morphogenesis / negative regulation of hair follicle development / 9+0 non-motile cilium / central nervous system neuron differentiation / regulation of somatic stem cell population maintenance / pancreas morphogenesis / epithelial-mesenchymal cell signaling / : / myoblast migration / atrial septum morphogenesis / determination of left/right asymmetry in lateral mesoderm / contact inhibition / spinal cord dorsal/ventral patterning / cerebellar cortex morphogenesis / left/right axis specification / ciliary tip / thalamus development / Activation of SMO / patched binding / somite development / positive regulation of branching involved in ureteric bud morphogenesis / type B pancreatic cell development / dorsal/ventral neural tube patterning / forebrain morphogenesis / cellular response to cholesterol / BBSome-mediated cargo-targeting to cilium / positive regulation of organ growth / smooth muscle tissue development / pattern specification process / mammary gland epithelial cell differentiation / dentate gyrus development / oxysterol binding / positive regulation of multicellular organism growth / commissural neuron axon guidance / dopaminergic neuron differentiation / positive regulation of smoothened signaling pathway / Class B/2 (Secretin family receptors) / cell fate specification / neural crest cell migration / cAMP-dependent protein kinase inhibitor activity / anterior/posterior pattern specification / ciliary membrane / positive regulation of mesenchymal cell proliferation / negative regulation of epithelial cell differentiation / smoothened signaling pathway / midgut development / hair follicle morphogenesis / positive regulation of neuroblast proliferation / heart looping / negative regulation of DNA binding / odontogenesis of dentin-containing tooth / protein kinase A catalytic subunit binding / neuroblast proliferation / Adenylate cyclase inhibitory pathway / protein sequestering activity / positive regulation of protein localization to cell cortex / endoplasmic reticulum-Golgi intermediate compartment / cell cortex region / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / vasculogenesis / Hedgehog 'off' state / skeletal muscle fiber development / regulation of mitotic spindle organization / cellular response to forskolin / homeostasis of number of cells within a tissue / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / centriole / negative regulation of protein phosphorylation / Regulation of insulin secretion / central nervous system development / epithelial cell proliferation / G protein-coupled receptor binding / G protein-coupled receptor activity / positive regulation of epithelial cell proliferation / astrocyte activation / multicellular organism growth / Hedgehog 'on' state / Olfactory Signaling Pathway / G-protein beta/gamma-subunit complex binding / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / cilium / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)
Similarity search - Function
Smoothened, transmembrane domain / Smoothened, cysteine-rich domain / Frizzled/Smoothened, transmembrane domain / Frizzled/Smoothened family membrane region / Frizzled/Smoothened family membrane region / Frizzled/secreted frizzled-related protein / Frizzled / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain ...Smoothened, transmembrane domain / Smoothened, cysteine-rich domain / Frizzled/Smoothened, transmembrane domain / Frizzled/Smoothened family membrane region / Frizzled/Smoothened family membrane region / Frizzled/secreted frizzled-related protein / Frizzled / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain / Frizzled (fz) domain profile. / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / G-protein alpha subunit, group I / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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
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 / Protein smoothened
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.14 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.
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: 0.0155
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.0155
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6xbm
  • Surface level: 0.0155
  • 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_22120.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of human SMO-Gi complex with 24(S),25-EC
Voxel sizeX=Y=Z: 0.832 Å
Density
Contour LevelBy AUTHOR: 0.0155 / Movie #1: 0.0155
Minimum - Maximum-0.04883239 - 0.086715326
Average (Standard dev.)0.00002718364 (±0.0023285986)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 232.96 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8320.8320.832
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z232.960232.960232.960
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-0.0490.0870.000

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Supplemental data

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Mask #1

Fileemd_22120_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Structure of human SMO-Gi complex with 24(S),25-EC

Fileemd_22120_half_map_1.map
AnnotationStructure of human SMO-Gi complex with 24(S),25-EC
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Structure of human SMO-Gi complex with 24(S),25-EC

Fileemd_22120_half_map_2.map
AnnotationStructure of human SMO-Gi complex with 24(S),25-EC
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : SMO-GI COMPLEX

EntireName: SMO-GI COMPLEX
Components
  • Complex: SMO-GI COMPLEX
    • Protein or peptide: Smoothened homolog
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • 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: scFv16
  • Ligand: 17-[3-(3,3-DIMETHYL-OXIRANYL)-1-METHYL-PROPYL]-10,13-DIMETHYL-2,3,4,7,8,9,10,11,12,13,14,15,16,17-TETRADECAHYDRO-1H-CYC LOPENTA[A]PHENANTHREN-3-OL

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Supramolecule #1: SMO-GI COMPLEX

SupramoleculeName: SMO-GI COMPLEX / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Smoothened homolog

MacromoleculeName: Smoothened homolog / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 71.786438 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAARPARGP ELPLLGLLLL LLLGDPGRGA ASSGNATGPG PRSAGGSARR SAAVTGPPPP LSHCGRAAPC EPLRYNVCLG SVLPYGATS TLLAGDSDSQ EEAHGKLVLW SGLRNAPRCW AVIQPLLCAV YMPKCENDRV ELPSRTLCQA TRGPCAIVER E RGWPDFLR ...String:
MAAARPARGP ELPLLGLLLL LLLGDPGRGA ASSGNATGPG PRSAGGSARR SAAVTGPPPP LSHCGRAAPC EPLRYNVCLG SVLPYGATS TLLAGDSDSQ EEAHGKLVLW SGLRNAPRCW AVIQPLLCAV YMPKCENDRV ELPSRTLCQA TRGPCAIVER E RGWPDFLR CTPDRFPEGC TNEVQNIKFN SSGQCEVPLV RTDNPKSWYE DVEGCGIQCQ NPLFTEAEHQ DMHSYIAAFG AV TGLCTLF TLATFVADWR NSNRYPAVIL FYVNACFFVG SIGWLAQFMD GARREIVCRA DGTMRLGEPT SNETLSCVII FVI VYYALM AGVVWFVVLT YAWHTSFKAL GTTYQPLSGK TSYFHLLTWS LPFVLTVAIL AVAQVDGDSV SGICFVGYKN YRYR AGFVL APIGLVLIVG GYFLIRGVMT LFSIKSNHPG LLSEKAASKI NETMLRLGIF GFLAFGFVLI TFSCHFYDFF NQAEW ERSF RDYVLCQANV TIGLPTKQPI PDCEIKNRPS LLVEKINLFA MFGTGIAMST WVWTKATLLI WRRTWCRLTG QSDDEP KRI KKSKMIAKAF SKRHELLQNP GQELSFSMHT VSHDGPVAGL AFDLNEPSAD VSSAWAQHVT KMVARRGAIL PQDISVT PV ATDYKDDDDK

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Macromolecule #2: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.415031 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.671102 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT ...String:
PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HESDINAICF FP NGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAGVLAGHDN RVS CLGVTD DGMAVATGSW DSFLKIWN

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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: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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Macromolecule #5: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 27.784896 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAAHHHHHH HH

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Macromolecule #6: 17-[3-(3,3-DIMETHYL-OXIRANYL)-1-METHYL-PROPYL]-10,13-DIMETHYL-2,3...

MacromoleculeName: 17-[3-(3,3-DIMETHYL-OXIRANYL)-1-METHYL-PROPYL]-10,13-DIMETHYL-2,3,4,7,8,9,10,11,12,13,14,15,16,17-TETRADECAHYDRO-1H-CYC LOPENTA[A]PHENANTHREN-3-OL
type: ligand / ID: 6 / Number of copies: 2 / Formula: CO1
Molecular weightTheoretical: 400.637 Da

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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

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 443107

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