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

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Entry
Database: EMDB / ID: EMD-4936
TitleStructure of PTCH1 bound to a modified Hedgehog ligand ShhN-C24II
Map data
Sample
  • Complex: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
    • Complex: Protein patched homolog 1 + GFP
      • Protein or peptide: Protein patched homolog 1,GFP-like fluorescent chromoprotein FP506, related
    • Complex: Sonic hedgehog protein
      • Protein or peptide: Sonic hedgehog protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: ZINC ION
KeywordsPatched / PTCH1 / Hedgehog / ShhN / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of nodal signaling pathway / neural plate axis specification / positive regulation of sclerotome development / negative regulation of ureter smooth muscle cell differentiation / positive regulation of ureter smooth muscle cell differentiation / negative regulation of kidney smooth muscle cell differentiation / positive regulation of kidney smooth muscle cell differentiation / morphogen activity / neural tube patterning / regulation of odontogenesis ...regulation of nodal signaling pathway / neural plate axis specification / positive regulation of sclerotome development / negative regulation of ureter smooth muscle cell differentiation / positive regulation of ureter smooth muscle cell differentiation / negative regulation of kidney smooth muscle cell differentiation / positive regulation of kidney smooth muscle cell differentiation / morphogen activity / neural tube patterning / regulation of odontogenesis / positive regulation of mesenchymal cell proliferation involved in ureter development / hedgehog receptor activity / Formation of lateral plate mesoderm / epithelial-mesenchymal cell signaling / polarity specification of anterior/posterior axis / smoothened binding / ventral midline development / metanephric mesenchymal cell proliferation involved in metanephros development / hedgehog family protein binding / cholesterol-protein transferase activity / neural tube formation / negative regulation of multicellular organism growth / HHAT G278V doesn't palmitoylate Hh-Np / negative thymic T cell selection / Ligand-receptor interactions / laminin-1 binding / limb morphogenesis / positive regulation of T cell differentiation in thymus / stem cell development / cerebellar granule cell precursor proliferation / determination of left/right asymmetry in lateral mesoderm / negative regulation of cholesterol efflux / lymphoid progenitor cell differentiation / cell development / pharyngeal system development / prostate gland development / somite development / male genitalia development / hindbrain development / negative regulation of cell division / patched binding / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / neuron fate commitment / smooth muscle tissue development / positive regulation of immature T cell proliferation in thymus / Activation of SMO / pattern specification process / self proteolysis / negative regulation of dopaminergic neuron differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / dopaminergic neuron differentiation / cellular response to cholesterol / metanephros development / Release of Hh-Np from the secreting cell / embryonic pattern specification / embryonic limb morphogenesis / positive regulation of smoothened signaling pathway / glycosaminoglycan binding / positive thymic T cell selection / positive regulation of alpha-beta T cell differentiation / neural crest cell migration / Formation of axial mesoderm / dorsal/ventral pattern formation / intein-mediated protein splicing / commissural neuron axon guidance / metanephric collecting duct development / response to alkaloid / cell fate specification / branching involved in blood vessel morphogenesis / regulation of smoothened signaling pathway / smoothened signaling pathway / regulation of protein localization to nucleus / branching involved in ureteric bud morphogenesis / oligodendrocyte differentiation / Class B/2 (Secretin family receptors) / embryonic digit morphogenesis / forebrain development / branching morphogenesis of an epithelial tube / midbrain development / spermatid development / ciliary membrane / neuroblast proliferation / heart looping / cholesterol binding / dendritic growth cone / androgen metabolic process / protein autoprocessing / positive regulation of cell division / regulation of proteolysis / vasculogenesis / lung development / positive regulation of cholesterol efflux / response to mechanical stimulus / response to retinoic acid / negative regulation of cell differentiation / negative regulation of osteoblast differentiation / axonal growth cone / thymus development / Hedgehog 'off' state / animal organ morphogenesis
Similarity search - Function
Transformer protein 2 N-terminal domain / Transmembrane receptor, patched / Hedgehog, N-terminal signalling domain / Hedgehog protein / Hedgehog protein, Hint domain / : / Hint module / Hedgehog amino-terminal signalling domain / Hedgehog signalling/DD-peptidase zinc-binding domain superfamily / : ...Transformer protein 2 N-terminal domain / Transmembrane receptor, patched / Hedgehog, N-terminal signalling domain / Hedgehog protein / Hedgehog protein, Hint domain / : / Hint module / Hedgehog amino-terminal signalling domain / Hedgehog signalling/DD-peptidase zinc-binding domain superfamily / : / Sterol-sensing domain of SREBP cleavage-activation / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain / Hint domain C-terminal / Hint (Hedgehog/Intein) domain C-terminal region / Intein N-terminal splicing region / Intein N-terminal splicing motif profile. / Hint domain N-terminal / Hint (Hedgehog/Intein) domain N-terminal region / Hint domain superfamily / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein
Similarity search - Domain/homology
Protein patched homolog 1 / Sonic hedgehog protein / GFP-like fluorescent chromoprotein FP506, related
Similarity search - Component
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.
History
DepositionMay 6, 2019-
Header (metadata) releaseOct 9, 2019-
Map releaseOct 9, 2019-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing 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

emd_4936.png

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

Histogram

Histogram (log scale)
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
Components
  • Complex: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
    • Complex: Protein patched homolog 1 + GFP
      • Protein or peptide: Protein patched homolog 1,GFP-like fluorescent chromoprotein FP506, related
    • Complex: Sonic hedgehog protein
      • Protein or peptide: Sonic hedgehog protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: ZINC ION

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Supramolecule #1: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II

SupramoleculeName: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2

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Supramolecule #2: Protein patched homolog 1 + GFP

SupramoleculeName: Protein patched homolog 1 + GFP / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Eimeria acervulina (eukaryote)

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Supramolecule #3: Sonic hedgehog protein

SupramoleculeName: Sonic hedgehog protein / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein patched homolog 1,GFP-like fluorescent chromoprotein FP50...

MacromoleculeName: Protein patched homolog 1,GFP-like fluorescent chromoprotein FP506, related
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Eimeria acervulina (eukaryote)
Molecular weightTheoretical: 163.846734 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASAGNAAEP QDRGGGGSGC IGAPGRPAGG GRRRRTGGLR RAAAPDRDYL HRPSYCDAAF ALEQISKGKA TGRKAPLWLR AKFQRLLFK LGCYIQKNCG KFLVVGLLIF GAFAVGLKAA NLETNVEELW VEVGGRVSRE LNYTRQKIGE EAMFNPQLMI Q TPKEEGAN ...String:
MASAGNAAEP QDRGGGGSGC IGAPGRPAGG GRRRRTGGLR RAAAPDRDYL HRPSYCDAAF ALEQISKGKA TGRKAPLWLR AKFQRLLFK LGCYIQKNCG KFLVVGLLIF GAFAVGLKAA NLETNVEELW VEVGGRVSRE LNYTRQKIGE EAMFNPQLMI Q TPKEEGAN VLTTEALLQH LDSALQASRV HVYMYNRQWK LEHLCYKSGE LITETGYMDQ IIEYLYPCLI ITPLDCFWEG AK LQSGTAY LLGKPPLRWT NFDPLEFLEE LKKINYQVDS WEEMLNKAEV GHGYMDRPCL NPADPDCPAT APNKNSTKPL DMA LVLNGG CHGLSRKYMH WQEELIVGGT VKNSTGKLVS AHALQTMFQL MTPKQMYEHF KGYEYVSHIN WNEDKAAAIL EAWQ RTYVE VVHQSVAQNS TQKVLSFTTT TLDDILKSFS DVSVIRVASG YLLMLAYACL TMLRWDCSKS QGAVGLAGVL LVALS VAAG LGLCSLIGIS FNAATTQVLP FLALGVGVDD VFLLAHAFSE TGQNKRIPFE DRTGECLKRT GASVALTSIS NVTAFF MAA LIPIPALRAF SLQAAVVVVF NFAMVLLIFP AILSMDLYRR EDRRLDIFCC FTSPCVSRVI QVEPQAYTDT HDNTRYS PP PPASSHSFAH ETQITMQSTV QLRTEYDPHT HVYYTTAEPR SEISVQPVTV TQDTLSCQSP ESTSSTRDLL SQFSDSSL H CLEPPCTKWT LSSFAEKHYA PFLLKPKAKV VVIFLFLGLL GVSLYGTTRV RDGLDLTDIV PRETREYDFI AAQFKYFSF YNMYIVTQKA DYPNIQHLLY DLHRSFSNVK YVMLEENKQL PKMWLHYFRD WLQGLQDAFD SDWETGKIMP NNYKNGSDDG VLAYKLLVQ TGSRDKPIDI SQLTKQRLVD ADGIINPSAF YIYLTAWVSN DPVAYAASQA NIRPHRPEWV HDKADYMPET R LRIPAAEP IEYAQFPFYL NGLRDTSDFV EAIEKVRTIC SNYTSLGLSS YPNGYPFLFW EQYIGLRHWL LLFISVVLAC TF LVCAVFL LNPWTAGIIV MVLALMTVEL FGMMGLIGIK LSAVPVVILI ASVGIGVEFT VHVALAFLTA IGDKNRRAVL ALE HMFAPV LDGAVSTLLG VLMLAGSEFD FIVRYFFAVL AILTILGVLN GLVLLPVLLS FFGPYPEVSP ANAAALEVLF QGPG GVSKG EELFTGVVPI LVELDGDVNG HKFSVSGEGE GDATYGKLTL KFICTTGKLP VPWPTLVTTF GYGLQCFARY PDHMK QHDF FKSAMPEGYV QERTIFFKDD GNYKTRAEVK FEGDTLVNRI ELKGIDFKED GNILGHKLEY NYNSHNVYIM ADKQKN GIK VNFKIRHNIE DGSVQLADHY QQNTPIGDGP VLLPDNHYLS YQSALSKDPN EKRDHMVLLE FVTAAGITLG MDELYKA AS AWSHPQFEKG GGSGGGSGGS AWSHPQFEK

UniProtKB: Protein patched homolog 1, GFP-like fluorescent chromoprotein FP506, related

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Macromolecule #2: Sonic hedgehog protein

MacromoleculeName: Sonic hedgehog protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 32.397508 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: MKKHHHHHHG SGMSDSEVNQ EAKPEVKPEV KPETHINLKV SDGSSEIFFK IKKTTPLRRL MEAFAKRQGK EMDSLRFLYD GIRIQADQT PEDLDMEDND IIEAHREQIG GIIGPGRGFG KRRHPKKLTP LAYKQFIPNV AEKTLGASGR YEGKISRNSE R FKELTPNY ...String:
MKKHHHHHHG SGMSDSEVNQ EAKPEVKPEV KPETHINLKV SDGSSEIFFK IKKTTPLRRL MEAFAKRQGK EMDSLRFLYD GIRIQADQT PEDLDMEDND IIEAHREQIG GIIGPGRGFG KRRHPKKLTP LAYKQFIPNV AEKTLGASGR YEGKISRNSE R FKELTPNY NPDIIFKDEE NTGADRLMTQ RCKDKLNALA ISVMNQWPGV KLRVTEGWDE DGHHSEESLH YEGRAVDITT SD RDRSKYG MLARLAVEAG FDWVYYESKA HIHCSVKAEN SVAAKSGG

UniProtKB: Sonic hedgehog protein

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #5: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 5 / Number of copies: 11 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #6: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 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: 8
GridMaterial: GOLD / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 44.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: -2.4 µm / Nominal defocus min: -0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 707620
Startup modelType of model: OTHER / Details: Initital model generated in cisTEM
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 200679
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 3.0)
FSC plot (resolution estimation)

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