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- PDB-6oev: Structure of human Patched1 in complex with native Sonic Hedgehog -

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Basic information

Entry
Database: PDB / ID: 6oev
TitleStructure of human Patched1 in complex with native Sonic Hedgehog
Components
  • Protein patched homolog 1
  • Sonic hedgehog protein
KeywordsMEMBRANE PROTEIN / tumor suppressor / Hh
Function / homology
Function and homology information


regulation of nodal signaling pathway / neural plate axis specification / morphogen activity / 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 / neural tube patterning / regulation of odontogenesis ...regulation of nodal signaling pathway / neural plate axis specification / morphogen activity / 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 / neural tube patterning / regulation of odontogenesis / positive regulation of mesenchymal cell proliferation involved in ureter development / hedgehog receptor activity / cerebellar granule cell precursor proliferation / Formation of lateral plate mesoderm / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / epithelial-mesenchymal cell signaling / polarity specification of anterior/posterior axis / neural tube formation / negative regulation of multicellular organism growth / ventral midline development / metanephric mesenchymal cell proliferation involved in metanephros development / smoothened binding / hedgehog family protein binding / cholesterol-protein transferase activity / 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 / determination of left/right asymmetry in lateral mesoderm / negative regulation of cholesterol efflux / lymphoid progenitor cell differentiation / metanephric collecting duct development / cell development / pharyngeal system development / somite development / prostate gland development / male genitalia development / neuroblast proliferation / hindbrain development / metanephros development / negative regulation of cell division / embryonic limb morphogenesis / neuron fate commitment / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / patched binding / smooth muscle tissue development / positive regulation of immature T cell proliferation in thymus / pattern specification process / self proteolysis / Activation of SMO / negative regulation of dopaminergic neuron differentiation / dopaminergic neuron differentiation / cellular response to cholesterol / androgen metabolic process / Release of Hh-Np from the secreting cell / oligodendrocyte differentiation / embryonic pattern specification / cell fate specification / positive regulation of smoothened signaling pathway / positive thymic T cell selection / glycosaminoglycan binding / positive regulation of alpha-beta T cell differentiation / dorsal/ventral pattern formation / neural crest cell migration / Formation of axial mesoderm / commissural neuron axon guidance / intein-mediated protein splicing / response to alkaloid / regulation of smoothened signaling pathway / branching involved in blood vessel morphogenesis / smoothened signaling pathway / regulation of protein localization to nucleus / branching involved in ureteric bud morphogenesis / embryonic digit morphogenesis / branching morphogenesis of an epithelial tube / Class B/2 (Secretin family receptors) / forebrain development / heart looping / midbrain development / spermatid development / ciliary membrane / cholesterol binding / thymus development / dendritic growth cone / protein autoprocessing / lung development / vasculogenesis / negative regulation of cell differentiation / positive regulation of cell division / regulation of proteolysis / T cell differentiation in thymus / positive regulation of cholesterol efflux / response to retinoic acid / response to mechanical stimulus / negative regulation of osteoblast differentiation / axonal growth cone / Hedgehog 'off' state
Similarity search - Function
Patched SSD / Transmembrane receptor, patched / Transformer protein 2 N-terminal domain / Muramoyl-pentapeptide Carboxypeptidase; domain 2 - #10 / Hedgehog, N-terminal signalling domain / Hedgehog protein / Hedgehog protein, Hint domain / : / Hint module / Hedgehog amino-terminal signalling domain ...Patched SSD / Transmembrane receptor, patched / Transformer protein 2 N-terminal domain / Muramoyl-pentapeptide Carboxypeptidase; domain 2 - #10 / Hedgehog, N-terminal signalling domain / Hedgehog protein / Hedgehog protein, Hint domain / : / Hint module / Hedgehog amino-terminal signalling domain / Muramoyl-pentapeptide Carboxypeptidase; domain 2 / 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Protein patched homolog 1 / Sonic hedgehog protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / Resolution: 3.8 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
DepositionMar 27, 2019Deposition site: RCSB / Processing site: RCSB
SupersessionApr 17, 2019ID: 6D4J
Revision 1.0Apr 17, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Dec 18, 2019Group: Other / Category: atom_sites / cell
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][1] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.Z_PDB
Revision 1.3Dec 25, 2019Group: Database references / Category: database_2
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / em_entity_assembly / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_close_contact / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _chem_comp.name / _chem_comp.type / _em_entity_assembly.entity_id_list / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_unobs_or_zero_occ_atoms.auth_asym_id / _pdbx_unobs_or_zero_occ_atoms.auth_seq_id / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Apr 2, 2025Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Protein patched homolog 1
C: Sonic hedgehog protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)181,9037
Polymers180,5472
Non-polymers1,3575
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5850 Å2
ΔGint-24 kcal/mol
Surface area50160 Å2

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Components

#1: Protein Protein patched homolog 1 / PTC1


Mass: 160714.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTCH1, PTCH / Production host: Homo sapiens (human) / References: UniProt: Q13635
#2: Protein Sonic hedgehog protein / SHH / HHG-1 / Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains / ShhNC


Mass: 19832.449 Da / Num. of mol.: 1 / Fragment: residues 24-197
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHH / Production host: Homo sapiens (human) / References: UniProt: Q15465
#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Protein patched homolog 1, Sonic hedgehog protein / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.121 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: NO
Specimen supportDetails: unspecified

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DARK FIELD
Image recordingElectron dose: 1.6 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0238 / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 194633 / Symmetry type: POINT
RefinementResolution: 3.8→83.4 Å / Cor.coef. Fo:Fc: 0.826 / SU B: 83.309 / SU ML: 0.963 / ESU R: 1.288
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.42085 --
obs0.42085 47359 99.99 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 172.875 Å2
Baniso -1Baniso -2Baniso -3
1--0.42 Å20.17 Å2-0.62 Å2
2--0.51 Å20.4 Å2
3----0.1 Å2
Refinement stepCycle: 1 / Total: 8546
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0040.0138729
ELECTRON MICROSCOPYr_bond_other_d0.0020.0178333
ELECTRON MICROSCOPYr_angle_refined_deg1.3831.62611867
ELECTRON MICROSCOPYr_angle_other_deg1.1871.5719168
ELECTRON MICROSCOPYr_dihedral_angle_1_deg7.68351124
ELECTRON MICROSCOPYr_dihedral_angle_2_deg31.58821.867391
ELECTRON MICROSCOPYr_dihedral_angle_3_deg17.44151357
ELECTRON MICROSCOPYr_dihedral_angle_4_deg12.9891546
ELECTRON MICROSCOPYr_chiral_restr0.0660.21162
ELECTRON MICROSCOPYr_gen_planes_refined0.0050.029842
ELECTRON MICROSCOPYr_gen_planes_other0.0020.021888
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it7.00718.6934511
ELECTRON MICROSCOPYr_mcbond_other7.00718.6924510
ELECTRON MICROSCOPYr_mcangle_it11.99528.0465630
ELECTRON MICROSCOPYr_mcangle_other11.99428.0475631
ELECTRON MICROSCOPYr_scbond_it5.71818.8424218
ELECTRON MICROSCOPYr_scbond_other5.71318.844216
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other10.45228.1176237
ELECTRON MICROSCOPYr_long_range_B_refined18.23210278
ELECTRON MICROSCOPYr_long_range_B_other18.23110279
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.8→3.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.568 3453 -
obs--99.97 %

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