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- EMDB-4939: Structure of PTCH1 bound to a modified Hedgehog ligand ShhN-C24II... -

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Basic information

Entry
Database: EMDB / ID: EMD-4939
TitleStructure of PTCH1 bound to a modified Hedgehog ligand ShhN-C24II: focused refinement of the membrane domain
Map dataFocused refinement of the membrane domain of PTCH1
Sample
  • Complex: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
    • Complex: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
      • Protein or peptide: Protein patched homolog 1
    • Complex: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
      • Protein or peptide: Sonic hedgehog protein
Function / homology
Function and homology information


neural plate axis specification / cell differentiation involved in kidney development / hedgehog receptor activity / response to chlorate / cell proliferation involved in metanephros development / smoothened binding / neural tube patterning / hedgehog family protein binding / Ligand-receptor interactions / hindlimb morphogenesis ...neural plate axis specification / cell differentiation involved in kidney development / hedgehog receptor activity / response to chlorate / cell proliferation involved in metanephros development / smoothened binding / neural tube patterning / hedgehog family protein binding / Ligand-receptor interactions / hindlimb morphogenesis / epidermal cell fate specification / spinal cord motor neuron differentiation / prostate gland development / Activation of SMO / negative regulation of cell division / patched binding / limb morphogenesis / somite development / dorsal/ventral neural tube patterning / cellular response to cholesterol / smooth muscle tissue development / pharyngeal system development / mammary gland duct morphogenesis / mammary gland epithelial cell differentiation / cell fate determination / commissural neuron axon guidance / metanephric collecting duct development / regulation of smoothened signaling pathway / dorsal/ventral pattern formation / Class B/2 (Secretin family receptors) / embryonic limb morphogenesis / cholesterol binding / ciliary membrane / smoothened signaling pathway / negative regulation of multicellular organism growth / branching involved in ureteric bud morphogenesis / positive regulation of epidermal cell differentiation / spermatid development / regulation of mitotic cell cycle / dendritic growth cone / positive regulation of cholesterol efflux / keratinocyte proliferation / negative regulation of keratinocyte proliferation / negative regulation of osteoblast differentiation / embryonic organ development / Hedgehog 'off' state / negative regulation of smoothened signaling pathway / axonal growth cone / response to mechanical stimulus / heart morphogenesis / response to retinoic acid / negative regulation of stem cell proliferation / cyclin binding / stem cell proliferation / neural tube closure / liver regeneration / caveola / protein localization to plasma membrane / animal organ morphogenesis / brain development / Hedgehog 'on' state / negative regulation of DNA-binding transcription factor activity / protein processing / endocytic vesicle membrane / regulation of protein localization / glucose homeostasis / response to estradiol / apical part of cell / heparin binding / midbody / in utero embryonic development / response to xenobiotic stimulus / intracellular membrane-bounded organelle / protein-containing complex binding / perinuclear region of cytoplasm / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / plasma membrane
Similarity search - Function
Transmembrane receptor, patched / Protein patched/dispatched / Patched family / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain
Similarity search - Domain/homology
Protein patched homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 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 7, 2019-
Header (metadata) releaseOct 9, 2019-
Map releaseOct 9, 2019-
UpdateOct 9, 2019-
Current statusOct 9, 2019Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.018
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.018
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_4939.png

Downloads & links

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Map

FileDownload / File: emd_4939.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFocused refinement of the membrane domain of PTCH1
Voxel sizeX=Y=Z: 0.8141 Å
Density
Contour LevelBy AUTHOR: 0.018 / Movie #1: 0.018
Minimum - Maximum-0.03598391 - 0.06646849
Average (Standard dev.)0.00006657017 (±0.001292825)
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-0.0360.0660.000

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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: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
      • Protein or peptide: Protein patched homolog 1
    • Complex: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
      • Protein or peptide: Sonic hedgehog protein

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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: all

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Supramolecule #2: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II

SupramoleculeName: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II

SupramoleculeName: Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24II
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)

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Macromolecule #1: Protein patched homolog 1

MacromoleculeName: Protein patched homolog 1 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASAGNAAEP QDRGGGGSGC IGAPGRPAGG GRRRRTGGLR RAAAPDRDYL HRPSYCDAAF ALEQISKGKA TGRKAPLWLR AKFQRLLFKL GCYIQKNCGK FLVVGLLIFG AFAVGLKAAN LETNVEELWV EVGGRVSREL NYTRQKIGEE AMFNPQLMIQ TPKEEGANVL ...String:
MASAGNAAEP QDRGGGGSGC IGAPGRPAGG GRRRRTGGLR RAAAPDRDYL HRPSYCDAAF ALEQISKGKA TGRKAPLWLR AKFQRLLFKL GCYIQKNCGK FLVVGLLIFG AFAVGLKAAN LETNVEELWV EVGGRVSREL NYTRQKIGEE AMFNPQLMIQ TPKEEGANVL TTEALLQHLD SALQASRVHV YMYNRQWKLE HLCYKSGELI TETGYMDQII EYLYPCLIIT PLDCFWEGAK LQSGTAYLLG KPPLRWTNFD PLEFLEELKK INYQVDSWEE MLNKAEVGHG YMDRPCLNPA DPDCPATAPN KNSTKPLDMA LVLNGGCHGL SRKYMHWQEE LIVGGTVKNS TGKLVSAHAL QTMFQLMTPK QMYEHFKGYE YVSHINWNED KAAAILEAWQ RTYVEVVHQS VAQNSTQKVL SFTTTTLDDI LKSFSDVSVI RVASGYLLML AYACLTMLRW DCSKSQGAVG LAGVLLVALS VAAGLGLCSL IGISFNAATT QVLPFLALGV GVDDVFLLAH AFSETGQNKR IPFEDRTGEC LKRTGASVAL TSISNVTAFF MAALIPIPAL RAFSLQAAVV VVFNFAMVLL IFPAILSMDL YRREDRRLDI FCCFTSPCVS RVIQVEPQAY TDTHDNTRYS PPPPASSHSF AHETQITMQS TVQLRTEYDP HTHVYYTTAE PRSEISVQPV TVTQDTLSCQ SPESTSSTRD LLSQFSDSSL HCLEPPCTKW TLSSFAEKHY APFLLKPKAK VVVIFLFLGL LGVSLYGTTR VRDGLDLTDI VPRETREYDF IAAQFKYFSF YNMYIVTQKA DYPNIQHLLY DLHRSFSNVK YVMLEENKQL PKMWLHYFRD WLQGLQDAFD SDWETGKIMP NNYKNGSDDG VLAYKLLVQT GSRDKPIDIS QLTKQRLVDA DGIINPSAFY IYLTAWVSND PVAYAASQAN IRPHRPEWVH DKADYMPETR LRIPAAEPIE YAQFPFYLNG LRDTSDFVEA IEKVRTICSN YTSLGLSSYP NGYPFLFWEQ YIGLRHWLLL FISVVLACTF LVCAVFLLNP WTAGIIVMVL ALMTVELFGM MGLIGIKLSA VPVVILIASV GIGVEFTVHV ALAFLTAIGD KNRRAVLALE HMFAPVLDGA VSTLLGVLML AGSEFDFIVR YFFAVLAILT ILGVLNGLVL LPVLLSFFGP YPEVSPANAA ALEVLFQGPG GVSKGEELFT GVVPILVELD GDVNGHKFSV SGEGEGDATY GKLTLKFICT TGKLPVPWPT LVTTFGYGLQ CFARYPDHMK QHDFFKSAMP EGYVQERTIF FKDDGNYKTR AEVKFEGDTL VNRIELKGID FKEDGNILGH KLEYNYNSHN VYIMADKQKN GIKVNFKIRH NIEDGSVQLA DHYQQNTPIG DGPVLLPDNH YLSYQSALSK DPNEKRDHMV LLEFVTAAGI TLGMDELYKA ASAWSHPQFE KGGGSGGGSG GSAWSHPQFE K

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Macromolecule #2: Sonic hedgehog protein

MacromoleculeName: Sonic hedgehog protein / type: protein_or_peptide / ID: 2 / Details: ShhN-C24II, a modified sonic hedgehog protein / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: MKKHHHHHHG SGMSDSEVNQ EAKPEVKPEV KPETHINLKV SDGSSEIFFK IKKTTPLRRL MEAFAKRQGK EMDSLRFLYD GIRIQADQTP EDLDMEDNDI IEAHREQIGG IIGPGRGFGK RRHPKKLTPL AYKQFIPNVA EKTLGASGRY EGKISRNSER FKELTPNYNP ...String:
MKKHHHHHHG SGMSDSEVNQ EAKPEVKPEV KPETHINLKV SDGSSEIFFK IKKTTPLRRL MEAFAKRQGK EMDSLRFLYD GIRIQADQTP EDLDMEDNDI IEAHREQIGG IIGPGRGFGK RRHPKKLTPL AYKQFIPNVA EKTLGASGRY EGKISRNSER FKELTPNYNP DIIFKDEENT GADRLMTQRC KDKLNALAIS VMNQWPGVKL RVTEGWDEDG HHSEESLHYE GRAVDITTSD RDRSKYGMLA RLAVEAGFDW VYYESKAHIH CSVKAENSVA AKSGG

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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
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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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: BRIGHT FIELDBright-field microscopy / 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
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 44.7 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 707620
CTF correctionSoftware - Name: Gctf
Startup modelType of model: OTHER / Details: Initital model generated in cisTEM
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 3.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0)
Details: Focused refinement with masking the detergent micelle and the ectodomain
Number images used: 200679
FSC plot (resolution estimation)

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