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- PDB-6n7h: Cryo-EM structure of the 2:1 hPtch1-Shhp complex -

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Entry
Database: PDB / ID: 6n7h
TitleCryo-EM structure of the 2:1 hPtch1-Shhp complex
Components
  • Protein patched homolog 1
  • Sonic hedgehog proteinSonic hedgehog
KeywordsPROTEIN BINDING / Receptor / RND family
Function / homology
Function and homology information


Hh mutants that don't undergo autocatalytic processing are degraded by ERAD / Hedgehog 'on' state / Activation of SMO / HHAT G278V abrogates palmitoylation of Hh-Np / Class B/2 (Secretin family receptors) / Release of Hh-Np from the secreting cell / Hedgehog ligand biogenesis / Hedgehog 'off' state / Ligand-receptor interactions / regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry ...Hh mutants that don't undergo autocatalytic processing are degraded by ERAD / Hedgehog 'on' state / Activation of SMO / HHAT G278V abrogates palmitoylation of Hh-Np / Class B/2 (Secretin family receptors) / Release of Hh-Np from the secreting cell / Hedgehog ligand biogenesis / Hedgehog 'off' state / Ligand-receptor interactions / regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry / cell proliferation involved in metanephros development / neural plate axis specification / hedgehog receptor activity / response to chlorate / cell differentiation involved in kidney development / smoothened signaling pathway involved in dorsal/ventral neural tube patterning / right lung development / positive regulation of skeletal muscle cell proliferation / positive regulation of kidney smooth muscle cell differentiation / negative regulation of kidney smooth muscle cell differentiation / negative regulation of ureter smooth muscle cell differentiation / tracheoesophageal septum formation / left lung development / regulation of mesenchymal cell proliferation involved in prostate gland development / positive regulation of sclerotome development / mesenchymal smoothened signaling pathway involved in prostate gland development / epithelial-mesenchymal signaling involved in prostate gland development / primary prostatic bud elongation / positive regulation of ureter smooth muscle cell differentiation / regulation of odontogenesis / regulation of prostatic bud formation / neural tube patterning / positive regulation of mesenchymal cell proliferation involved in ureter development / spinal cord dorsal/ventral patterning / smoothened binding / hindgut morphogenesis / morphogen activity / polarity specification of anterior/posterior axis / cerebellar granule cell precursor proliferation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / striated muscle tissue development / positive regulation of immature T cell proliferation in thymus / bud outgrowth involved in lung branching / epidermal cell fate specification / metanephric mesenchymal cell proliferation involved in metanephros development / positive regulation of striated muscle cell differentiation / hedgehog family protein binding / negative regulation of alpha-beta T cell differentiation / determination of left/right asymmetry in lateral mesoderm / positive regulation of hh target transcription factor activity / ventral midline development / lung epithelium development / artery development / formation of anatomical boundary / smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation / hindlimb morphogenesis / trachea morphogenesis / telencephalon regionalization / laminin-1 binding / spinal cord motor neuron differentiation / stem cell development / negative regulation of mesenchymal cell apoptotic process / salivary gland cavitation / myotube differentiation / intermediate filament organization / mammary gland duct morphogenesis / positive regulation of T cell differentiation in thymus / neuroblast proliferation / negative regulation of cholesterol efflux / renal system development / limb morphogenesis / dorsal/ventral neural tube patterning / patched binding / somite development / negative regulation of transcription elongation from RNA polymerase II promoter / cellular response to cholesterol / keratinocyte proliferation / negative regulation of cell division / embryonic digestive tract morphogenesis / lymphoid progenitor cell differentiation / lung lobe morphogenesis / negative regulation of smoothened signaling pathway / limb bud formation / embryonic foregut morphogenesis / epithelial cell proliferation involved in salivary gland morphogenesis / negative thymic T cell selection / embryonic skeletal system development / negative regulation of multicellular organism growth / pharyngeal system development / hindbrain development / dorsal/ventral pattern formation / mesenchymal cell proliferation involved in lung development / thalamus development / negative regulation of dopaminergic neuron differentiation / animal organ formation / male genitalia development / positive regulation of epidermal cell differentiation / mammary gland epithelial cell differentiation / metanephros development / ectoderm development
Patched family / Sterol-sensing domain / Intein N-terminal splicing motif profile. / Sterol-sensing domain (SSD) profile. / Hedgehog, N-terminal signalling domain / Hedgehog protein / Hedgehog protein, Hint domain / Protein patched/dispatched / Hint domain C-terminal / Hint domain N-terminal ...Patched family / Sterol-sensing domain / Intein N-terminal splicing motif profile. / Sterol-sensing domain (SSD) profile. / Hedgehog, N-terminal signalling 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
Protein patched homolog 1 / Sonic hedgehog protein
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsYan, N. / Gong, X. / Qian, H.W.
Funding supportUnited States , 1件
OrganizationGrant numberCountry
National Science Foundation (United States)DMR-1420541United States
CitationJournal: Nat Commun / Year: 2019
Title: Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm.
Authors: Hongwu Qian / Pingping Cao / Miaohui Hu / Shuai Gao / Nieng Yan / Xin Gong /
Abstract: The Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of Hh receptor Patched (Ptch) by the Hh ligands relieves suppression of ...The Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of Hh receptor Patched (Ptch) by the Hh ligands relieves suppression of signaling cascades. Here, we report the cryo-EM structure of tetrameric Ptch1 in complex with the palmitoylated N-terminal signaling domain of human Sonic hedgehog (ShhN) at a 4:2 stoichiometric ratio. The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers. Each dimer binds to one ShhN through two distinct inhibitory interfaces, one mainly through the N-terminal peptide and the palmitoyl moiety of ShhN and the other through the Ca-mediated interface on ShhN. Map comparison reveals that the cholesteryl moiety of native ShhN occupies a recently identified extracellular steroid binding pocket in Ptch1. Our structure elucidates the tetrameric assembly of Ptch1 and suggests an asymmetric mode of action of the Hh ligands for inhibiting the potential cholesterol transport activity of Ptch1.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Nov 27, 2018 / Release: May 29, 2019
RevisionDateData content typeGroupCategoryItemProviderType
1.0May 29, 2019Structure modelrepositoryInitial release
1.1Jun 12, 2019Structure modelData collection / Database referencescitation / citation_author_citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)325,40526
Polymers319,9733
Non-polymers5,43223
Water0
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein/peptide , 2 types, 3 molecules ABC

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


Mass: 150189.578 Da / Num. of mol.: 2
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/peptide Sonic hedgehog protein / Sonic hedgehog / SHH / HHG-1 / Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains / ShhNC


Mass: 19594.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHH / Production host: Homo sapiens (human) / References: UniProt: Q15465

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Non-polymers , 5 types, 23 molecules

#3: Chemical
ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE


Mass: 221.208 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: C8H15NO6 / N-Acetylglucosamine
#4: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C27H46O / Cholesterol
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Zinc
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca / Calcium
#7: Chemical ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H32O2 / Palmitic acid

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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: Patch1 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: 1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 15 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen 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
Image recordingElectron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM software
IDNameCategory
4GctfCTF correction
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
13RELION3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 171590 / Symmetry type: POINT

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