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- PDB-6rmg: Structure of PTCH1 bound to a modified Hedgehog ligand ShhN-C24II -

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Basic information

Entry
Database: PDB / ID: 6rmg
TitleStructure of PTCH1 bound to a modified Hedgehog ligand ShhN-C24II
Components
  • Protein patched homolog 1,GFP-like fluorescent chromoprotein FP506, related
  • Sonic hedgehog proteinSonic hedgehog
KeywordsMEMBRANE PROTEIN / Patched / PTCH1 / Hedgehog / ShhN
Function / homology
Function and homology information


regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry / right lung development / left lung development / primary prostatic bud elongation / regulation of mesenchymal cell proliferation involved in prostate gland development / mesenchymal smoothened signaling pathway involved in prostate gland development / positive regulation of skeletal muscle cell proliferation / epithelial-mesenchymal signaling involved in prostate gland development / positive regulation of kidney smooth muscle cell differentiation / negative regulation of kidney smooth muscle cell differentiation ...regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry / right lung development / left lung development / primary prostatic bud elongation / regulation of mesenchymal cell proliferation involved in prostate gland development / mesenchymal smoothened signaling pathway involved in prostate gland development / positive regulation of skeletal muscle cell proliferation / epithelial-mesenchymal signaling involved in prostate gland development / positive regulation of kidney smooth muscle cell differentiation / negative regulation of kidney smooth muscle cell differentiation / positive regulation of ureter smooth muscle cell differentiation / negative regulation of ureter smooth muscle cell differentiation / positive regulation of sclerotome development / tracheoesophageal septum formation / neural plate axis specification / positive regulation of mesenchymal cell proliferation involved in ureter development / regulation of odontogenesis / cell proliferation involved in metanephros development / hedgehog receptor activity / cell differentiation involved in kidney development / smoothened signaling pathway involved in dorsal/ventral neural tube patterning / response to chlorate / spinal cord dorsal/ventral patterning / morphogen activity / polarity specification of anterior/posterior axis / neural tube patterning / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / cerebellar granule cell precursor proliferation / striated muscle tissue development / bud outgrowth involved in lung branching / hindgut morphogenesis / regulation of prostatic bud formation / metanephric mesenchymal cell proliferation involved in metanephros development / positive regulation of striated muscle cell differentiation / negative regulation of alpha-beta T cell differentiation / smoothened binding / epidermal cell fate specification / positive regulation of hh target transcription factor activity / determination of left/right asymmetry in lateral mesoderm / hedgehog family protein binding / formation of anatomical boundary / lung epithelium development / ventral midline development / smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation / trachea morphogenesis / artery development / telencephalon regionalization / hindlimb morphogenesis / laminin-1 binding / salivary gland cavitation / spinal cord motor neuron differentiation / stem cell development / cell development / myotube differentiation / negative regulation of mesenchymal cell apoptotic process / intermediate filament organization / positive regulation of T cell differentiation in thymus / neuroblast proliferation / negative regulation of cholesterol efflux / dorsal/ventral neural tube patterning / limb morphogenesis / prostate gland development / positive regulation of immature T cell proliferation in thymus / patched binding / lung lobe morphogenesis / negative regulation of cell division / somite development / mammary gland duct morphogenesis / keratinocyte proliferation / epithelial cell proliferation involved in salivary gland morphogenesis / embryonic foregut morphogenesis / lymphoid progenitor cell differentiation / limb bud formation / embryonic digestive tract morphogenesis / pattern specification process / cellular response to cholesterol / hindbrain development / negative thymic T cell selection / ectoderm development / smooth muscle tissue development / mesenchymal cell proliferation involved in lung development / negative regulation of dopaminergic neuron differentiation / negative regulation of multicellular organism growth / animal organ formation / dorsal/ventral pattern formation / pharyngeal system development / thalamus development / negative regulation of transcription elongation from RNA polymerase II promoter / positive regulation of skeletal muscle tissue development / male genitalia development / dopaminergic neuron differentiation / mammary gland epithelial cell differentiation / neuron fate commitment / metanephros development / embryonic skeletal system development / regulation of protein localization to nucleus / regulation of proteolysis / commissural neuron axon guidance / positive regulation of epithelial cell proliferation involved in prostate gland development / positive regulation of smoothened signaling pathway
Sterol-sensing domain / Hedgehog protein / Patched family / Green fluorescent protein / Hedgehog amino-terminal signalling domain / Green fluorescent protein-related / Green fluorescent protein, GFP / Hint domain superfamily / Transmembrane receptor, patched / Hedgehog signalling/DD-peptidase zinc-binding domain superfamily ...Sterol-sensing domain / Hedgehog protein / Patched family / Green fluorescent protein / Hedgehog amino-terminal signalling domain / Green fluorescent protein-related / Green fluorescent protein, GFP / Hint domain superfamily / Transmembrane receptor, patched / Hedgehog signalling/DD-peptidase zinc-binding domain superfamily / Green fluorescent protein / Hedgehog protein, Hint domain / Protein patched/dispatched / Hint domain N-terminal / Hint domain C-terminal / Intein N-terminal splicing region / Hedgehog, N-terminal signalling domain / Muramoyl-pentapeptide Carboxypeptidase; domain 2 - #10 / Muramoyl-pentapeptide Carboxypeptidase; domain 2 / 2-Layer Sandwich / Alpha Beta
Protein patched homolog 1 / Sonic hedgehog protein / GFP-like fluorescent chromoprotein FP506, related
Biological speciesHomo sapiens (human)
Eimeria acervulina (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsKorkhov, V.M. / Qi, C.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation150665 Switzerland
CitationJournal: Sci Adv / Year: 2019
Title: Structural basis of sterol recognition by human hedgehog receptor PTCH1.
Authors: Chao Qi / Giulio Di Minin / Irene Vercellino / Anton Wutz / Volodymyr M Korkhov /
Abstract: Hedgehog signaling is central in embryonic development and tissue regeneration. Disruption of the pathway is linked to genetic diseases and cancer. Binding of the secreted ligand, Sonic hedgehog ...Hedgehog signaling is central in embryonic development and tissue regeneration. Disruption of the pathway is linked to genetic diseases and cancer. Binding of the secreted ligand, Sonic hedgehog (ShhN) to its receptor Patched (PTCH1) activates the signaling pathway. Here, we describe a 3.4-Å cryo-EM structure of the human PTCH1 bound to ShhN, a modified hedgehog ligand mimicking its palmitoylated form. The membrane-embedded part of PTCH1 is surrounded by 10 sterol molecules at the inner and outer lipid bilayer portion of the protein. The annular sterols interact at multiple sites with both the sterol-sensing domain (SSD) and the SSD-like domain (SSDL), which are located on opposite sides of PTCH1. The structure reveals a possible route for sterol translocation across the lipid bilayer by PTCH1 and homologous transporters.
Validation Report
SummaryFull reportAbout validation report
History
DepositionMay 6, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 9, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Other / Category: atom_sites / cell
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.Z_PDB
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...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_struct_conn_angle / 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_atom_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_entity_id / _atom_site.type_symbol / _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_struct_conn_angle.ptnr2_label_asym_id / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

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Assembly

Deposited unit
A: Protein patched homolog 1,GFP-like fluorescent chromoprotein FP506, related
B: Sonic hedgehog protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)203,19420
Polymers196,2442
Non-polymers6,95018
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area4000 Å2
ΔGint-19 kcal/mol
Surface area52220 Å2
MethodPISA

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Protein patched homolog 1,GFP-like fluorescent chromoprotein FP506, related / PTC1


Mass: 163846.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Eimeria acervulina (eukaryote)
Gene: PTCH1, PTCH, EAH_00062270 / Plasmid: pACMV / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: Q13635, UniProt: U6GSR1
#2: Protein Sonic hedgehog protein / Sonic hedgehog / SHH / HHG-1 / Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains / ShhNC


Mass: 32397.508 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHH / Plasmid: pET28a / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: Q15465

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Sugars , 2 types, 6 molecules

#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


GlcNAc

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GlcNAc

Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: obtained synthetically / 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

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Non-polymers , 2 types, 12 molecules

#5: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C31H50O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-ZN / ZINC ION / Zinc


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

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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

Component
IDNameTypeEntity IDParent-IDSource
1Complex of PTCH1 with a modified Hedgehog ligand ShhN-C24IICOMPLEX#1-#20MULTIPLE SOURCES
2Protein patched homolog 1 + GFPCOMPLEX#11RECOMBINANT
3Sonic hedgehog proteinSonic hedgehogCOMPLEX#21RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Eimeria acervulina (eukaryote)5801
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
12Homo sapiens (human)9606HEK293S GnTI-
23Escherichia coli BL21 (bacteria)511693
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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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: BRIGHT FIELDBright-field microscopy / Nominal defocus max: -2400 nm / Nominal defocus min: -800 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 44.7 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.11.1_2575: / Classification: refinement
EM software
IDNameVersionCategory
1RELIONparticle selection
2SerialEMimage acquisition
4GctfCTF correction
7Coot0.8.9.1model fitting
9RELIONinitial Euler assignment
10RELION3final Euler assignment
11RELION3classification
12RELION33D reconstruction
13PHENIX1.11.1-2575model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 707620
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 200679 / Num. of class averages: 1 / Symmetry type: POINT

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