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- EMDB-0358: Cryo-EM structure of tetrameric Ptch1 in complex with ShhNp (form II) -

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Basic information

Entry
Database: EMDB / ID: EMD-0358
TitleCryo-EM structure of tetrameric Ptch1 in complex with ShhNp (form II)
Map dataem-volume_P1
Sample
  • Organelle or cellular component: Patch1
    • Protein or peptide: Protein patched homolog 1
  • Protein or peptide: Sonic hedgehog protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: ZINC ION
  • Ligand: CALCIUM ION
  • Ligand: PALMITIC ACID
KeywordsReceptor / RND family / PROTEIN BINDING
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 / regulation of odontogenesis / positive regulation of mesenchymal cell proliferation involved in ureter development ...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 / 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 / neural tube patterning / smoothened binding / ventral midline development / metanephric mesenchymal cell proliferation involved in metanephros development / hedgehog family protein binding / cholesterol-protein transferase activity / neural tube formation / HHAT G278V doesn't palmitoylate Hh-Np / Ligand-receptor interactions / negative regulation of multicellular organism growth / laminin-1 binding / limb morphogenesis / stem cell development / positive regulation of T cell differentiation in thymus / determination of left/right asymmetry in lateral mesoderm / negative regulation of cholesterol efflux / negative thymic T cell selection / cell development / cerebellar granule cell precursor proliferation / prostate gland development / pharyngeal system development / male genitalia development / hindbrain development / negative regulation of cell division / patched binding / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / somite development / neuron fate commitment / lymphoid progenitor cell differentiation / smooth muscle tissue development / 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 / positive regulation of immature T cell proliferation in thymus / cellular response to cholesterol / metanephros development / Release of Hh-Np from the secreting cell / embryonic pattern specification / embryonic limb morphogenesis / glycosaminoglycan binding / positive regulation of alpha-beta T cell differentiation / Formation of axial mesoderm / positive thymic T cell selection / intein-mediated protein splicing / dorsal/ventral pattern formation / metanephric collecting duct development / response to alkaloid / commissural neuron axon guidance / positive regulation of smoothened signaling pathway / regulation of smoothened signaling pathway / cell fate specification / neural crest cell migration / regulation of protein localization to nucleus / branching involved in blood vessel morphogenesis / branching involved in ureteric bud morphogenesis / Class B/2 (Secretin family receptors) / smoothened signaling pathway / oligodendrocyte differentiation / embryonic digit morphogenesis / forebrain development / branching morphogenesis of an epithelial tube / midbrain development / ciliary membrane / cholesterol binding / neuroblast proliferation / heart looping / spermatid development / dendritic growth cone / androgen metabolic process / protein autoprocessing / positive regulation of cell division / regulation of proteolysis / vasculogenesis / positive regulation of cholesterol efflux / response to retinoic acid / negative regulation of cell differentiation / response to mechanical stimulus / lung development / 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
Similarity search - Domain/homology
Protein patched homolog 1 / Sonic hedgehog protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.5 Å
AuthorsYan N / Gong X
Funding support United States, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)DMR-1420541 United States
CitationJournal: Nat Commun / Year: 2019
Title: Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm.
Authors: Hongwu Qian / Pingping Cao / Miaohui Hu / Shuai Gao / Nieng Yan / Xin Gong /
Abstract: The Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of Hh receptor Patched (Ptch) by the Hh ligands relieves suppression of ...The Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of Hh receptor Patched (Ptch) by the Hh ligands relieves suppression of signaling cascades. Here, we report the cryo-EM structure of tetrameric Ptch1 in complex with the palmitoylated N-terminal signaling domain of human Sonic hedgehog (ShhN) at a 4:2 stoichiometric ratio. The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers. Each dimer binds to one ShhN through two distinct inhibitory interfaces, one mainly through the N-terminal peptide and the palmitoyl moiety of ShhN and the other through the Ca-mediated interface on ShhN. Map comparison reveals that the cholesteryl moiety of native ShhN occupies a recently identified extracellular steroid binding pocket in Ptch1. Our structure elucidates the tetrameric assembly of Ptch1 and suggests an asymmetric mode of action of the Hh ligands for inhibiting the potential cholesterol transport activity of Ptch1.
History
DepositionNov 27, 2018-
Header (metadata) releaseDec 19, 2018-
Map releaseMay 29, 2019-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6n7k
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6n7k
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0358.png

Downloads & links

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Map

FileDownload / File: emd_0358.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationem-volume_P1
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.11 Å/pix.
x 280 pix.
= 311.92 Å		1.11 Å/pix.
x 280 pix.
= 311.92 Å		1.11 Å/pix.
x 280 pix.
= 311.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.114 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03 / Movie #1: 0.015
Minimum - Maximum-0.017574318 - 0.07663275
Average (Standard dev.)0.00065977516 (±0.00578557)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 311.91998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.1141.1141.114
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z311.920311.920311.920
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-0.0180.0770.001

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Supplemental data

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Additional map: em-additional-volume P1

Fileemd_0358_additional.map
Annotationem-additional-volume_P1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Patch1

EntireName: Patch1
Components
  • Organelle or cellular component: Patch1
    • Protein or peptide: Protein patched homolog 1
  • Protein or peptide: Sonic hedgehog protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: ZINC ION
  • Ligand: CALCIUM ION
  • Ligand: PALMITIC ACID

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Supramolecule #1: Patch1

SupramoleculeName: Patch1 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein patched homolog 1

MacromoleculeName: Protein patched homolog 1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 150.189578 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADYKDDDDK SGPDEVDASG RMASAGNAAE PQDRGGGGSG CIGAPGRPAG GGRRRRTGGL RRAAAPDRDY LHRPSYCDAA FALEQISKG KATGRKAPLW LRAKFQRLLF KLGCYIQKNC GKFLVVGLLI FGAFAVGLKA ANLETNVEEL WVEVGGRVSR E LNYTRQKI ...String:
MADYKDDDDK SGPDEVDASG RMASAGNAAE PQDRGGGGSG CIGAPGRPAG GGRRRRTGGL RRAAAPDRDY LHRPSYCDAA FALEQISKG KATGRKAPLW LRAKFQRLLF KLGCYIQKNC GKFLVVGLLI FGAFAVGLKA ANLETNVEEL WVEVGGRVSR E LNYTRQKI GEEAMFNPQL MIQTPKEEGA NVLTTEALLQ HLDSALQASR VHVYMYNRQW KLEHLCYKSG ELITETGYMD QI IEYLYPC LIITPLDCFW EGAKLQSGTA YLLGKPPLRW TNFDPLEFLE ELKKINYQVD SWEEMLNKAE VGHGYMDRPC LNP ADPDCP ATAPNKNSTK PLDMALVLNG GCHGLSRKYM HWQEELIVGG TVKNSTGKLV SAHALQTMFQ LMTPKQMYEH FKGY EYVSH INWNEDKAAA ILEAWQRTYV EVVHQSVAQN STQKVLSFTT TTLDDILKSF SDVSVIRVAS GYLLMLAYAC LTMLR WDCS KSQGAVGLAG VLLVALSVAA GLGLCSLIGI SFNAATTQVL PFLALGVGVD DVFLLAHAFS ETGQNKRIPF EDRTGE CLK RTGASVALTS ISNVTAFFMA ALIPIPALRA FSLQAAVVVV FNFAMVLLIF PAILSMDLYR REDRRLDIFC CFTSPCV SR VIQVEPQAYT DTHDNTRYSP PPPYSSHSFA HETQITMQST VQLRTEYDPH THVYYTTAEP RSEISVQPVT VTQDTLSC Q SPESTSSTRD LLSQFSDSSL HCLEPPCTKW TLSSFAEKHY APFLLKPKAK VVVIFLFLGL LGVSLYGTTR VRDGLDLTD IVPRETREYD FIAAQFKYFS FYNMYIVTQK ADYPNIQHLL YDLHRSFSNV KYVMLEENKQ LPKMWLHYFR DWLQGLQDAF DSDWETGKI MPNNYKNGSD DGVLAYKLLV QTGSRDKPID ISQLTKQRLV DADGIINPSA FYIYLTAWVS NDPVAYAASQ A NIRPHRPE WVHDKADYMP ETRLRIPAAE PIEYAQFPFY LNGLRDTSDF VEAIEKVRTI CSNYTSLGLS SYPNGYPFLF WE QYIGLRH WLLLFISVVL ACTFLVCAVF LLNPWTAGII VMVLALMTVE LFGMMGLIGI KLSAVPVVIL IASVGIGVEF TVH VALAFL TAIGDKNRRA VLALEHMFAP VLDGAVSTLL GVLMLAGSEF DFIVRYFFAV LAILTILGVL NGLVLLPVLL SFFG PYPEV SPANGLNRLP TPSPEPPPSV VRFAMPPGHT HSGSDSSDSE YSSQTTVSGL SEELRHYEAQ QGAGGPAHQV IVEAT ENPV FAHSTVVHPE SRHHPPSNPR QQPHLDSGSL PPGRQGQQPR RDLEGSDEVD AVEGSHHHHH HHHHH

UniProtKB: Protein patched homolog 1

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Macromolecule #2: Sonic hedgehog protein

MacromoleculeName: Sonic hedgehog protein / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.594039 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
CGPGRGFGKR RHPKKLTPLA YKQFIPNVAE KTLGASGRYE GKISRNSERF KELTPNYNPD IIFKDEENTG ADRLMTQRCK DKLNALAIS VMNQWPGVKL RVTEGWDEDG HHSEESLHYE GRAVDITTSD RDRSKYGMLA RLAVEAGFDW VYYESKAHIH C SVKAENSV AAKSGG

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: 20 / 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

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 10 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #6: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 6 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #7: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #8: PALMITIC ACID

MacromoleculeName: PALMITIC ACID / type: ligand / ID: 8 / Number of copies: 2 / Formula: PLM
Molecular weightTheoretical: 256.424 Da
Chemical component information

ChemComp-PLM:
PALMITIC ACID

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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

Concentration15 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: Gctf / Type: NONE
Startup modelType of model: RANDOM CONICAL TILT
Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 25510
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION

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