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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 protein
KeywordsMEMBRANE PROTEIN / Patched / PTCH1 / Hedgehog / ShhN
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 / neural tube patterning / regulation of odontogenesis ...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 / neural tube patterning / 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 / smoothened binding / ventral midline development / metanephric mesenchymal cell proliferation involved in metanephros development / hedgehog family protein binding / cholesterol-protein transferase activity / neural tube formation / negative regulation of multicellular organism growth / 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 / cerebellar granule cell precursor proliferation / determination of left/right asymmetry in lateral mesoderm / negative regulation of cholesterol efflux / lymphoid progenitor cell differentiation / cell development / pharyngeal system development / prostate gland development / somite development / male genitalia development / hindbrain development / negative regulation of cell division / patched binding / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / neuron fate commitment / smooth muscle tissue development / positive regulation of immature T cell proliferation in thymus / Activation of SMO / pattern specification process / self proteolysis / negative regulation of dopaminergic neuron differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / dopaminergic neuron differentiation / cellular response to cholesterol / metanephros development / Release of Hh-Np from the secreting cell / embryonic pattern specification / embryonic limb morphogenesis / positive regulation of smoothened signaling pathway / glycosaminoglycan binding / positive thymic T cell selection / positive regulation of alpha-beta T cell differentiation / neural crest cell migration / Formation of axial mesoderm / dorsal/ventral pattern formation / intein-mediated protein splicing / commissural neuron axon guidance / metanephric collecting duct development / response to alkaloid / cell fate specification / branching involved in blood vessel morphogenesis / regulation of smoothened signaling pathway / smoothened signaling pathway / regulation of protein localization to nucleus / branching involved in ureteric bud morphogenesis / oligodendrocyte differentiation / Class B/2 (Secretin family receptors) / embryonic digit morphogenesis / forebrain development / branching morphogenesis of an epithelial tube / midbrain development / spermatid development / ciliary membrane / neuroblast proliferation / heart looping / cholesterol binding / dendritic growth cone / androgen metabolic process / protein autoprocessing / positive regulation of cell division / regulation of proteolysis / vasculogenesis / lung development / positive regulation of cholesterol efflux / response to mechanical stimulus / response to retinoic acid / negative regulation of cell differentiation / negative regulation of osteoblast differentiation / axonal growth cone / thymus development / Hedgehog 'off' state / animal organ morphogenesis
Similarity search - Function
Patched SSD / Transformer protein 2 N-terminal domain / Transmembrane receptor, patched / 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 / Transformer protein 2 N-terminal domain / Transmembrane receptor, patched / 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 / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
CHOLESTEROL HEMISUCCINATE / Protein patched homolog 1 / Sonic hedgehog protein / GFP-like fluorescent chromoprotein FP506, related
Similarity search - Component
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.
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
Revision 2.1Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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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
Water00
1


  • Idetical with deposited unit
  • defined by author&software
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 / 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


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-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.: 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


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

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Details

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

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 proteinCOMPLEX#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 FIELD / Nominal defocus max: -2400 nm / Nominal defocus min: -800 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder 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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