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- PDB-6oeu: Structure of human Patched1 -

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Basic information

Entry
Database: PDB / ID: 6oeu
TitleStructure of human Patched1
ComponentsProtein patched homolog 1
KeywordsMEMBRANE PROTEIN / tumor suppressor
Function / homology
Function and homology information


hedgehog receptor activity / cell proliferation involved in metanephros development / neural plate axis specification / cell differentiation involved in kidney development / smoothened signaling pathway involved in dorsal/ventral neural tube patterning / response to chlorate / neural tube patterning / smoothened binding / epidermal cell fate specification / hedgehog family protein binding ...hedgehog receptor activity / cell proliferation involved in metanephros development / neural plate axis specification / cell differentiation involved in kidney development / smoothened signaling pathway involved in dorsal/ventral neural tube patterning / response to chlorate / neural tube patterning / smoothened binding / epidermal cell fate specification / hedgehog family protein binding / hindlimb morphogenesis / spinal cord motor neuron differentiation / limb morphogenesis / prostate gland development / negative regulation of cell division / mammary gland duct morphogenesis / keratinocyte proliferation / patched binding / somite development / cellular response to cholesterol / negative regulation of multicellular organism growth / pharyngeal system development / smooth muscle tissue development / mammary gland epithelial cell differentiation / dorsal/ventral pattern formation / commissural neuron axon guidance / positive regulation of cholesterol efflux / negative regulation of smoothened signaling pathway / cell fate determination / positive regulation of epidermal cell differentiation / regulation of smoothened signaling pathway / smoothened signaling pathway / metanephric collecting duct development / ciliary membrane / embryonic limb morphogenesis / negative regulation of osteoblast differentiation / cholesterol binding / branching involved in ureteric bud morphogenesis / dendritic growth cone / regulation of mitotic cell cycle / heart morphogenesis / embryonic organ development / protein processing / axonal growth cone / protein localization to plasma membrane / cyclin binding / response to mechanical stimulus / liver regeneration / response to retinoic acid / regulation of protein localization / animal organ morphogenesis / neural tube closure / caveola / endocytic vesicle membrane / midbody / negative regulation of DNA-binding transcription factor activity / brain development / negative regulation of epithelial cell proliferation / glucose homeostasis / apical part of cell / heparin binding / response to estradiol / in utero embryonic development / response to drug / postsynaptic density / intracellular membrane-bounded organelle / protein-containing complex binding / perinuclear region of cytoplasm / positive regulation of transcription, DNA-templated / negative regulation of transcription by RNA polymerase II / integral component of membrane / plasma membrane / nucleus
Patched family / Transmembrane receptor, patched / Protein patched/dispatched / Sterol-sensing domain
Protein patched homolog 1 / polysac:dglcpnacb1-4dglcpnacb1-roh:
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / Resolution: 3.5 Å
AuthorsQi, X. / Li, X. / Wang, J.
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.
Validation Report
SummaryFull reportAbout validation report
History
DepositionMar 27, 2019Deposition site: RCSB / Processing site: RCSB
SupersessionApr 10, 2019ID: 6D4H
Revision 1.0Apr 10, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Other / Category: atom_sites
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]
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 / 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.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _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

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Assembly

Deposited unit
A: Protein patched homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)163,4095
Polymers161,7111
Non-polymers1,6984
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area1480 Å2
ΔGint19 kcal/mol
Surface area44850 Å2

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Components

#1: Protein Protein patched homolog 1 / PTC1


Mass: 161711.406 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: 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.: 4
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

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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: Ptc / Type: COMPLEX / Entity ID: #1 / 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

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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: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 789118 / Symmetry type: POINT
RefinementResolution: 3.5→78.2 Å / Cor.coef. Fo:Fc: 0.772 / SU B: 82.336 / SU ML: 1.098 / ESU R: 1.691
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.45616 --
Obs0.45616 35251 100 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 120.582 Å2
Baniso -1Baniso -2Baniso -3
1--3.94 Å2-0.22 Å2-1.03 Å2
2--1.33 Å20.37 Å2
3---2.61 Å2
Refinement stepCycle: 1 / Total: 7206
Refine LS restraints
Refinement-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0040.0137362
ELECTRON MICROSCOPYr_bond_other_d0.0030.0177059
ELECTRON MICROSCOPYr_angle_refined_deg1.3931.61910036
ELECTRON MICROSCOPYr_angle_other_deg1.2511.55916208
ELECTRON MICROSCOPYr_dihedral_angle_1_deg7.4975961
ELECTRON MICROSCOPYr_dihedral_angle_2_deg34.25822.097310
ELECTRON MICROSCOPYr_dihedral_angle_3_deg16.881151116
ELECTRON MICROSCOPYr_dihedral_angle_4_deg12.7071533
ELECTRON MICROSCOPYr_chiral_restr0.0690.2996
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.028323
ELECTRON MICROSCOPYr_gen_planes_other0.0020.021584
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_it513.2073853
ELECTRON MICROSCOPYr_mcbond_other4.99513.2073852
ELECTRON MICROSCOPYr_mcangle_it8.6419.8164811
ELECTRON MICROSCOPYr_mcangle_other8.63919.8164812
ELECTRON MICROSCOPYr_scbond_it3.516133509
ELECTRON MICROSCOPYr_scbond_other3.516133509
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other6.46319.4645226
ELECTRON MICROSCOPYr_long_range_B_refined13.2688503
ELECTRON MICROSCOPYr_long_range_B_other13.2688503
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.5→3.591 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.685 2611 -
Obs--100 %

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