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- PDB-6e1h: Structure of 2:1 human Ptch1-Shh-N complex -

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Basic information

Entry
Database: PDB / ID: 6e1h
TitleStructure of 2:1 human Ptch1-Shh-N complex
Components
  • Protein patched homolog 1
  • Sonic hedgehog protein N-product
KeywordsMEMBRANE PROTEIN / tumor suppressor
Function / homologyIntein N-terminal splicing motif profile. / Hh mutants that don't undergo autocatalytic processing are degraded by ERAD / Release of Hh-Np from the secreting cell / Hedgehog 'off' state / Ligand-receptor interactions / Hedgehog 'on' state / Activation of SMO / HHAT G278V abrogates palmitoylation of Hh-Np / Hedgehog ligand biogenesis / Class B/2 (Secretin family receptors) ...Intein N-terminal splicing motif profile. / Hh mutants that don't undergo autocatalytic processing are degraded by ERAD / Release of Hh-Np from the secreting cell / Hedgehog 'off' state / Ligand-receptor interactions / Hedgehog 'on' state / Activation of SMO / HHAT G278V abrogates palmitoylation of Hh-Np / Hedgehog ligand biogenesis / Class B/2 (Secretin family receptors) / Hedgehog, N-terminal signalling domain / Sterol-sensing domain / Hedgehog protein / Hedgehog protein, Hint domain / Protein patched/dispatched / Hint domain C-terminal / Hint domain N-terminal / Transmembrane receptor, patched / Intein N-terminal splicing region / Hedgehog signalling/DD-peptidase zinc-binding domain superfamily / Hint domain superfamily / Hint module / Hedgehog amino-terminal signalling domain / Patched family / Sterol-sensing domain (SSD) profile. / regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry / response to chlorate / neural plate axis specification / hedgehog receptor activity / cell proliferation involved in metanephros development / cell differentiation involved in kidney development / smoothened signaling pathway involved in dorsal/ventral neural tube patterning / neural tube patterning / mesenchymal smoothened signaling pathway involved in prostate gland development / positive regulation of ureter smooth muscle cell differentiation / right lung development / epithelial-mesenchymal signaling involved in prostate gland development / negative regulation of ureter smooth muscle cell differentiation / regulation of mesenchymal cell proliferation involved in prostate gland development / left lung development / negative regulation of kidney smooth muscle cell differentiation / tracheoesophageal septum formation / positive regulation of kidney smooth muscle cell differentiation / positive regulation of sclerotome development / positive regulation of skeletal muscle cell proliferation / primary prostatic bud elongation / positive regulation of mesenchymal cell proliferation involved in ureter development / smoothened binding / regulation of odontogenesis / regulation of prostatic bud formation / spinal cord dorsal/ventral patterning / hindgut morphogenesis / polarity specification of anterior/posterior axis / morphogen activity / epidermal cell fate specification / cerebellar granule cell precursor proliferation / bud outgrowth involved in lung branching / striated muscle tissue development / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / hedgehog family protein binding / positive regulation of immature T cell proliferation in thymus / metanephric mesenchymal cell proliferation involved in metanephros development / determination of left/right asymmetry in lateral mesoderm / negative regulation of alpha-beta T cell differentiation / positive regulation of striated muscle cell differentiation / ventral midline development / positive regulation of hh target transcription factor activity / artery development / lung epithelium development / formation of anatomical boundary / smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation / hindlimb morphogenesis / trachea morphogenesis / telencephalon regionalization / spinal cord motor neuron differentiation / laminin-1 binding / negative regulation of mesenchymal cell apoptotic process / myotube differentiation / salivary gland cavitation / stem cell development / intermediate filament organization / mammary gland duct morphogenesis / pattern specification process / positive regulation of T cell differentiation in thymus / hindbrain development / dorsal/ventral neural tube patterning / negative regulation of cholesterol efflux / patched binding / neuroblast proliferation / lymphoid progenitor cell differentiation / limb morphogenesis / somite development / embryonic foregut morphogenesis / negative regulation of multicellular organism growth / negative regulation of cell division / cellular response to cholesterol / negative regulation of smoothened signaling pathway / positive regulation of cholesterol efflux / renal system development / mesenchymal cell proliferation involved in lung development
Function and homology information
Specimen sourceHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / 3.5 Å resolution
AuthorsQi, X. / Li, X.
CitationJournal: Science / Year: 2018
Title: Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex.
Authors: Xiaofeng Qi / Philip Schmiege / Elias Coutavas / Xiaochun Li
Abstract: Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH ...Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Our 3.5-angstrom resolution cryo-electron microscopy structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Jul 9, 2018 / Release: Aug 29, 2018
RevisionDateData content typeGroupCategoryItemProviderType
1.0Aug 29, 2018Structure modelrepositoryInitial release
1.1Sep 5, 2018Structure modelData collection / Database referencescitation_citation.pdbx_database_id_PubMed / _citation.title
1.2Oct 17, 2018Structure modelData collection / Database referencescitation_citation.journal_volume

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Assembly

Deposited unit
A: Protein patched homolog 1
C: Sonic hedgehog protein N-product
B: Protein patched homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)341,4076
Polyers341,2613
Non-polymers1463
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)7660
ΔGint (kcal/M)-79
Surface area (Å2)88560

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Components

#1: Protein/peptide Protein patched homolog 1 / PTC1


Mass: 160714.406 Da / Num. of mol.: 2 / Source: (gene. exp.) Homo sapiens (human) / Gene: PTCH1, PTCH / Production host: Homo sapiens (human) / References: UniProt: Q13635
#2: Protein/peptide Sonic hedgehog protein N-product / / SHH / HHG-1 / Sonic hedgehog protein / ShhNC


Mass: 19832.449 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: SHH / Production host: Homo sapiens (human) / References: UniProt: Q15465
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Formula: Zn / Zinc
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Formula: Ca / Calcium

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Ptc / Type: COMPLEX / Entity ID: 1, 2 / Source: RECOMBINANT
Molecular weightValue: 0.265 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
MicroscopyMicroscope model: 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: 5.8.0222 / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 77712 / Symmetry type: POINT
RefineCorrelation coeff Fo to Fc: 0.791 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS / Overall SU B: 73.029 / Overall SU ML: 0.917 / Overall ESU R: 1.045
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Solvent computationSolvent ion probe radii: 0.8 Å / Solvent shrinkage radii: 0.8 Å / Solvent vdw probe radii: 1.2 Å / Solvent model details: MASK
Displacement parametersB iso mean: 80.671 Å2 / Aniso B11: -1.08 Å2 / Aniso B12: -0.14 Å2 / Aniso B13: -0.9 Å2 / Aniso B22: 1.59 Å2 / Aniso B23: 0.02 Å2 / Aniso B33: -0.51 Å2
Least-squares processHighest resolution: 3.5 Å / Number reflection obs: 104753 / Percent reflection obs: 99.99
Number of atoms included #1Total: 16669
Refine LS restraints
Refine IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0050.01417076
ELECTRON MICROSCOPYr_bond_other_d0.0020.01715768
ELECTRON MICROSCOPYr_angle_refined_deg1.1591.64123208
ELECTRON MICROSCOPYr_angle_other_deg0.9331.62936685
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.1705.0002115
ELECTRON MICROSCOPYr_dihedral_angle_2_deg26.42722.166808
ELECTRON MICROSCOPYr_dihedral_angle_3_deg13.09115.0002815
ELECTRON MICROSCOPYr_dihedral_angle_4_deg9.60615.00087
ELECTRON MICROSCOPYr_chiral_restr0.0680.2002197
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.02019044
ELECTRON MICROSCOPYr_gen_planes_other0.0020.0203352
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_it1.8488.3628473
ELECTRON MICROSCOPYr_mcbond_other1.8488.3628472
ELECTRON MICROSCOPYr_mcangle_it2.86412.53810581
ELECTRON MICROSCOPYr_mcangle_other2.86412.53910582
ELECTRON MICROSCOPYr_scbond_it0.0728.2688603
ELECTRON MICROSCOPYr_scbond_other0.0728.2688603
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other0.30112.39812628
ELECTRON MICROSCOPYr_long_range_B_refined3.25520539
ELECTRON MICROSCOPYr_long_range_B_other3.25520536
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
Refine LS shellHighest resolution: 3.5 Å / R factor R free: 0 / R factor R work: 0.727 / Lowest resolution: 3.591 Å / Number reflection R free: 0 / Number reflection R work: 7606 / Total number of bins used: 20 / Percent reflection obs: 99.99

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