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- EMDB-7796: Structure of human Patched1 in complex with native Sonic Hedgehog -

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Basic information

Entry
Database: EMDB / ID: EMD-7796
TitleStructure of human Patched1 in complex with native Sonic Hedgehog
Map dataA protein structure
Sample
  • Complex: Ptc
    • Protein or peptide: Protein patched homolog 1
    • Protein or peptide: Sonic hedgehog protein
  • Ligand: N-ACETYL-D-GLUCOSAMINE
  • Ligand: ZINC ION
  • Ligand: PALMITIC ACID
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 / HHAT G278V doesn't palmitoylate Hh-Np / Ligand-receptor interactions / laminin-1 binding / neural tube formation / determination of left/right asymmetry in lateral mesoderm / negative regulation of cholesterol efflux / positive regulation of T cell differentiation in thymus / cerebellar granule cell precursor proliferation / cell development / prostate gland development / limb morphogenesis / stem cell development / negative regulation of cell division / patched binding / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / somite development / hindbrain development / neuron fate commitment / Activation of SMO / pattern specification process / self proteolysis / smooth muscle tissue development / negative thymic T cell selection / negative regulation of dopaminergic neuron differentiation / male genitalia development / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / dopaminergic neuron differentiation / pharyngeal system development / positive regulation of immature T cell proliferation in thymus / cellular response to cholesterol / lymphoid progenitor cell differentiation / Release of Hh-Np from the secreting cell / glycosaminoglycan binding / embryonic pattern specification / positive regulation of alpha-beta T cell differentiation / Formation of axial mesoderm / positive thymic T cell selection / metanephros development / intein-mediated protein splicing / metanephric collecting duct development / response to alkaloid / commissural neuron axon guidance / positive regulation of smoothened signaling pathway / regulation of smoothened signaling pathway / dorsal/ventral pattern formation / regulation of protein localization to nucleus / embryonic limb morphogenesis / cell fate specification / Class B/2 (Secretin family receptors) / negative regulation of multicellular organism growth / neural crest cell migration / embryonic digit morphogenesis / smoothened signaling pathway / branching involved in ureteric bud morphogenesis / branching involved in blood vessel morphogenesis / branching morphogenesis of an epithelial tube / cholesterol binding / midbrain development / forebrain development / ciliary membrane / heart looping / dendritic growth cone / oligodendrocyte differentiation / spermatid development / neuroblast proliferation / androgen metabolic process / protein autoprocessing / positive regulation of cell division / regulation of proteolysis / positive regulation of cholesterol efflux / negative regulation of cell differentiation / response to retinoic acid / vasculogenesis / response to mechanical stimulus / negative regulation of osteoblast differentiation / axonal growth cone / Hedgehog 'off' state / lung development / thymus development / liver regeneration
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 / Resolution: 3.5 Å
AuthorsQi X / Li X
CitationJournal: Nature / Year: 2018
Title: Structures of human Patched and its complex with native palmitoylated sonic hedgehog.
Authors: Xiaofeng Qi / Philip Schmiege / Elias Coutavas / Jiawei Wang / Xiaochun Li /
Abstract: Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms. Whereas deficient HH signalling leads to birth defects, unrestrained HH ...Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms. Whereas deficient HH signalling leads to birth defects, unrestrained HH signalling is implicated in human cancers. N-terminally palmitoylated HH releases the repression of Patched to the oncoprotein smoothened (SMO); however, the mechanism by which HH recognizes Patched is unclear. Here we report cryo-electron microscopy structures of human patched 1 (PTCH1) alone and in complex with the N-terminal domain of 'native' sonic hedgehog (native SHH-N has both a C-terminal cholesterol and an N-terminal fatty-acid modification), at resolutions of 3.5 Å and 3.8 Å, respectively. The structure of PTCH1 has internal two-fold pseudosymmetry in the transmembrane core, which features a sterol-sensing domain and two homologous extracellular domains, resembling the architecture of Niemann-Pick C1 (NPC1) protein. The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface, which is distinct from that reported for SHH-N co-receptors. Our biochemical assays show that SHH-N may use another interface, one that is required for its co-receptor binding, to recruit PTCH1 in the absence of a covalently attached palmitate. Our work provides atomic insights into the recognition of the N-terminal domain of HH (HH-N) by PTCH1, offers a structural basis for cooperative binding of HH-N to various receptors and serves as a molecular framework for HH signalling and its malfunction in disease.
History
DepositionApr 18, 2018-
Header (metadata) releaseJul 4, 2018-
Map releaseJul 11, 2018-
UpdateApr 17, 2019-
Current statusApr 17, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.55
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.55
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6oev
  • Surface level: 0.55
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7796.png

Downloads & links

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Map

FileDownload / File: emd_7796.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationA protein structure
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 256 pix.
= 256. Å		1 Å/pix.
x 256 pix.
= 256. Å		1 Å/pix.
x 256 pix.
= 256. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy EMDB: 0.55 / Movie #1: 0.55
Minimum - Maximum-1.3252866 - 2.2768981
Average (Standard dev.)0.0033889343 (±0.08910678)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 256.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z111
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z256.000256.000256.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-1.3252.2770.003

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Supplemental data

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Sample components

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Entire : Ptc

EntireName: Ptc
Components
  • Complex: Ptc
    • Protein or peptide: Protein patched homolog 1
    • Protein or peptide: Sonic hedgehog protein
  • Ligand: N-ACETYL-D-GLUCOSAMINE
  • Ligand: ZINC ION
  • Ligand: PALMITIC ACID

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Supramolecule #1: Ptc

SupramoleculeName: Ptc / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightExperimental: 121 KDa

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Macromolecule #1: Protein patched homolog 1

MacromoleculeName: Protein patched homolog 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 160.714406 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 PPYSSHSFAH 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 ANGLNRLPTP SPEP PPSVV RFAMPPGHTH SGSDSSDSEY SSQTTVSGLS EELRHYEAQQ GAGGPAHQVI VEATENPVFA HSTVVHPESR HHPPS NPRQ QPHLDSGSLP PGRQGQQPRR DPPREGLWPP PYRPRRDAFE ISTEGHSGPS NRARWGPRGA RSHNPRNPAS TAMGSS VPG YCQPITTVTA SASVTVAVHP PPVPGPGRNP RGGLCPGYPE TDHGLFEDPH VPFHVRCERR DSKVEVIELQ DVECEER PR GSSSN

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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: 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

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Macromolecule #3: N-ACETYL-D-GLUCOSAMINE

MacromoleculeName: N-ACETYL-D-GLUCOSAMINE / type: ligand / ID: 3 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: PALMITIC ACID

MacromoleculeName: PALMITIC ACID / type: ligand / ID: 5 / Number of copies: 1 / 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

Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 1.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5u73

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 789118
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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