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- EMDB-4936: Structure of PTCH1 bound to a modified Hedgehog ligand ShhN-C24II -

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Basic information

Entry
Database: EMDB / ID: EMD-4936
TitleStructure of PTCH1 bound to a modified Hedgehog ligand ShhN-C24II
Map data
SampleComplex of PTCH1 with a modified Hedgehog ligand ShhN-C24II:
(Protein patched homolog ...) x 2 / (Sonic hedgehog ...) x 2 / (ligand) x 3
Function / homology
Function and homology information


regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry / negative regulation of kidney smooth muscle cell differentiation / right lung development / left lung development / primary prostatic bud elongation / epithelial-mesenchymal signaling involved in prostate gland development / regulation of mesenchymal cell proliferation involved in prostate gland development / positive regulation of skeletal muscle cell proliferation / positive regulation of sclerotome development / mesenchymal smoothened signaling pathway involved in prostate gland development ...regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry / negative regulation of kidney smooth muscle cell differentiation / right lung development / left lung development / primary prostatic bud elongation / epithelial-mesenchymal signaling involved in prostate gland development / regulation of mesenchymal cell proliferation involved in prostate gland development / positive regulation of skeletal muscle cell proliferation / positive regulation of sclerotome development / mesenchymal smoothened signaling pathway involved in prostate gland development / negative regulation of ureter smooth muscle cell differentiation / tracheoesophageal septum formation / positive regulation of ureter smooth muscle cell differentiation / positive regulation of kidney smooth muscle cell differentiation / positive regulation of mesenchymal cell proliferation involved in ureter development / regulation of odontogenesis / hedgehog receptor activity / neural plate axis specification / cell proliferation involved in metanephros development / response to chlorate / smoothened signaling pathway involved in dorsal/ventral neural tube patterning / morphogen activity / spinal cord dorsal/ventral patterning / cell differentiation involved in kidney development / polarity specification of anterior/posterior axis / neural tube patterning / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / cerebellar granule cell precursor proliferation / striated muscle tissue development / hindgut morphogenesis / bud outgrowth involved in lung branching / metanephric mesenchymal cell proliferation involved in metanephros development / regulation of prostatic bud formation / positive regulation of striated muscle cell differentiation / negative regulation of alpha-beta T cell differentiation / smoothened binding / epidermal cell fate specification / positive regulation of hh target transcription factor activity / determination of left/right asymmetry in lateral mesoderm / lung epithelium development / hedgehog family protein binding / formation of anatomical boundary / ventral midline development / smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation / trachea morphogenesis / artery development / telencephalon regionalization / hindlimb morphogenesis / laminin-1 binding / spinal cord motor neuron differentiation / salivary gland cavitation / stem cell development / myotube differentiation / cell development / negative regulation of mesenchymal cell apoptotic process / intermediate filament organization / positive regulation of T cell differentiation in thymus / neuroblast proliferation / negative regulation of cholesterol efflux / dorsal/ventral neural tube patterning / limb morphogenesis / prostate gland development / positive regulation of immature T cell proliferation in thymus / somite development / patched binding / lung lobe morphogenesis / negative regulation of cell division / keratinocyte proliferation / mammary gland duct morphogenesis / epithelial cell proliferation involved in salivary gland morphogenesis / embryonic foregut morphogenesis / lymphoid progenitor cell differentiation / limb bud formation / pattern specification process / cellular response to cholesterol / embryonic digestive tract morphogenesis / negative thymic T cell selection / hindbrain development / ectoderm development / smooth muscle tissue development / mesenchymal cell proliferation involved in lung development / negative regulation of multicellular organism growth / negative regulation of dopaminergic neuron differentiation / animal organ formation / dorsal/ventral pattern formation / pharyngeal system development / thalamus development / negative regulation of transcription elongation from RNA polymerase II promoter / positive regulation of skeletal muscle tissue development / male genitalia development / dopaminergic neuron differentiation / mammary gland epithelial cell differentiation / neuron fate commitment / metanephros development / regulation of proteolysis / embryonic skeletal system development / regulation of protein localization to nucleus / commissural neuron axon guidance / positive regulation of epithelial cell proliferation involved in prostate gland development / positive regulation of cholesterol efflux
Hedgehog protein / Hint domain superfamily / Hedgehog protein, Hint domain / Protein patched/dispatched / Hint domain C-terminal / Transmembrane receptor, patched / Intein N-terminal splicing region / Green fluorescent protein / Hedgehog signalling/DD-peptidase zinc-binding domain superfamily / Green fluorescent protein-related ...Hedgehog protein / Hint domain superfamily / Hedgehog protein, Hint domain / Protein patched/dispatched / Hint domain C-terminal / Transmembrane receptor, patched / Intein N-terminal splicing region / Green fluorescent protein / Hedgehog signalling/DD-peptidase zinc-binding domain superfamily / Green fluorescent protein-related / Hint domain N-terminal / Sterol-sensing domain / Green fluorescent protein, GFP / Hedgehog, N-terminal signalling domain
Protein patched homolog 1 / Sonic hedgehog protein / GFP-like fluorescent chromoprotein FP506, related
Biological speciesEimeria acervulina (eukaryote) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsKorkhov VM / Qi C
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Swiss National Science Foundation150665 Switzerland
CitationJournal: Sci Adv / Year: 2019
Title: Structural basis of sterol recognition by human hedgehog receptor PTCH1.
Authors: Chao Qi / Giulio Di Minin / Irene Vercellino / Anton Wutz / Volodymyr M Korkhov /
Abstract: Hedgehog signaling is central in embryonic development and tissue regeneration. Disruption of the pathway is linked to genetic diseases and cancer. Binding of the secreted ligand, Sonic hedgehog ...Hedgehog signaling is central in embryonic development and tissue regeneration. Disruption of the pathway is linked to genetic diseases and cancer. Binding of the secreted ligand, Sonic hedgehog (ShhN) to its receptor Patched (PTCH1) activates the signaling pathway. Here, we describe a 3.4-Å cryo-EM structure of the human PTCH1 bound to ShhN, a modified hedgehog ligand mimicking its palmitoylated form. The membrane-embedded part of PTCH1 is surrounded by 10 sterol molecules at the inner and outer lipid bilayer portion of the protein. The annular sterols interact at multiple sites with both the sterol-sensing domain (SSD) and the SSD-like domain (SSDL), which are located on opposite sides of PTCH1. The structure reveals a possible route for sterol translocation across the lipid bilayer by PTCH1 and homologous transporters.
Validation ReportPDB-ID: 6rmg

SummaryFull reportAbout validation report
History
DepositionMay 6, 2019-
Header (metadata) releaseOct 9, 2019-
Map releaseOct 9, 2019-
UpdateJul 29, 2020-
Current statusJul 29, 2020Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6rmg
  • Surface level: 0.016
  • 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_4936.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.81 Å/pix.
x 300 pix.
= 244.23 Å
0.81 Å/pix.
x 300 pix.
= 244.23 Å
0.81 Å/pix.
x 300 pix.
= 244.23 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8141 Å
Density
Contour LevelBy AUTHOR: 0.016 / Movie #1: 0.016
Minimum - Maximum-0.03301779 - 0.072111376
Average (Standard dev.)0.000116659816 (±0.001629073)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 244.23001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.81410.81410.8141
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z244.230244.230244.230
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ224224224
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.0330.0720.000

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Supplemental data

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Sample components

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Entire Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II

EntireName: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
Number of components: 8

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Component #1: protein, Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II

ProteinName: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
Recombinant expression: No

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Component #2: protein, Protein patched homolog 1 + GFP

ProteinName: Protein patched homolog 1 + GFP / Recombinant expression: No
SourceSpecies: Eimeria acervulina (eukaryote)
Source (engineered)Expression System: Homo sapiens (human) / Cell of expression system: HEK293S GnTI-

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Component #3: protein, Sonic hedgehog protein

ProteinName: Sonic hedgehog proteinSonic hedgehog / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli BL21 (bacteria)

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Component #4: protein, Protein patched homolog 1,GFP-like fluorescent chromopro...

ProteinName: Protein patched homolog 1,GFP-like fluorescent chromoprotein FP506, related
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 163.846734 kDa
SourceSpecies: Eimeria acervulina (eukaryote)
Source (engineered)Expression System: Homo sapiens (human)

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Component #5: protein, Sonic hedgehog protein

ProteinName: Sonic hedgehog proteinSonic hedgehog / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 32.397508 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli BL21 (bacteria)

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Component #6: ligand, 2-acetamido-2-deoxy-beta-D-glucopyranose

LigandName: 2-acetamido-2-deoxy-beta-D-glucopyranose / Number of Copies: 5 / Recombinant expression: No
MassTheoretical: 0.221208 kDa

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Component #7: ligand, CHOLESTEROL HEMISUCCINATE

LigandName: CHOLESTEROL HEMISUCCINATE / Number of Copies: 11 / Recombinant expression: No
MassTheoretical: 0.486726 kDa

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Component #8: ligand, ZINC ION

LigandName: ZINC ION / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 6.540905 MDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 8
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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: 44.7 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD / Defocus: -800.0 - -2400.0 nm
Specimen HolderModel: FEI TITAN KRIOS AUTOGRID HOLDER
CameraDetector: GATAN K2 QUANTUM (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 200679
3D reconstructionSoftware: RELION / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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Atomic model buiding

Output model

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