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- PDB-6o3c: Crystal structure of active Smoothened bound to SAG21k, cholester... -

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Basic information

Entry
Database: PDB / ID: 6o3c
TitleCrystal structure of active Smoothened bound to SAG21k, cholesterol, and NbSmo8
Components
  • NbSmo8
  • Smoothened homolog
KeywordsSIGNALING PROTEIN / GPCR / Signaling / Hedgehog / Smoothened / Cholesterol / SAG
Function / homology
Function and homology information


BBSome-mediated cargo-targeting to cilium / regulation of localization / ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / Activation of SMO / regulation of heart morphogenesis / contact inhibition / negative regulation of hair follicle development / negative regulation of hepatocyte proliferation / central nervous system neuron differentiation ...BBSome-mediated cargo-targeting to cilium / regulation of localization / ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / Activation of SMO / regulation of heart morphogenesis / contact inhibition / negative regulation of hair follicle development / negative regulation of hepatocyte proliferation / central nervous system neuron differentiation / 9+0 non-motile cilium / pancreas morphogenesis / regulation of somatic stem cell population maintenance / mesenchymal to epithelial transition / epithelial-mesenchymal cell signaling / myoblast migration / atrial septum morphogenesis / determination of left/right asymmetry in lateral mesoderm / Hedgehog 'on' state / spinal cord dorsal/ventral patterning / axon extension involved in axon guidance / positive regulation of hepatic stellate cell activation / cell development / left/right axis specification / Hedgehog 'off' state / thalamus development / somite development / patched binding / forebrain morphogenesis / cellular response to cholesterol / type B pancreatic cell development / dorsal/ventral neural tube patterning / positive regulation of branching involved in ureteric bud morphogenesis / positive regulation of organ growth / smooth muscle tissue development / pattern specification process / cerebellar cortex morphogenesis / mammary gland epithelial cell differentiation / dentate gyrus development / positive regulation of multicellular organism growth / dopaminergic neuron differentiation / commissural neuron axon guidance / oxysterol binding / positive regulation of neural precursor cell proliferation / positive regulation of smoothened signaling pathway / digestive tract development / dorsal/ventral pattern formation / positive regulation of vascular associated smooth muscle cell migration / determination of left/right symmetry / cell fate specification / neural crest cell migration / cAMP-dependent protein kinase inhibitor activity / ciliary membrane / anterior/posterior pattern specification / positive regulation of mesenchymal cell proliferation / negative regulation of epithelial cell differentiation / midgut development / smoothened signaling pathway / hair follicle morphogenesis / positive regulation of neuroblast proliferation / heart looping / negative regulation of DNA binding / odontogenesis of dentin-containing tooth / dendritic growth cone / protein kinase A catalytic subunit binding / endoplasmic reticulum-Golgi intermediate compartment / protein localization to nucleus / hair follicle development / developmental growth / neuroblast proliferation / vasculogenesis / embryonic organ development / positive regulation of autophagy / skeletal muscle fiber development / axonal growth cone / heart morphogenesis / homeostasis of number of cells within a tissue / epithelial cell differentiation / protein sequestering activity / centriole / ossification / negative regulation of protein phosphorylation / epithelial cell proliferation / central nervous system development / caveola / positive regulation of epithelial cell proliferation / astrocyte activation / G protein-coupled receptor activity / multicellular organism growth / cerebral cortex development / cilium / positive regulation of protein import into nucleus / osteoblast differentiation / protein import into nucleus / endocytic vesicle membrane / late endosome / gene expression / regulation of gene expression / in utero embryonic development / negative regulation of neuron apoptotic process
Similarity search - Function
Smoothened, transmembrane domain / Smoothened, cysteine-rich domain / Frizzled/Smoothened, transmembrane domain / Frizzled/Smoothened family membrane region / Frizzled/Smoothened family membrane region / Frizzled/secreted frizzled-related protein / Frizzled / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain ...Smoothened, transmembrane domain / Smoothened, cysteine-rich domain / Frizzled/Smoothened, transmembrane domain / Frizzled/Smoothened family membrane region / Frizzled/Smoothened family membrane region / Frizzled/secreted frizzled-related protein / Frizzled / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain / Frizzled (fz) domain profile. / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2.
Similarity search - Domain/homology
CHOLESTEROL / Chem-LKD / (2S)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / PHOSPHATE ION / Protein smoothened
Similarity search - Component
Biological speciesMus musculus (house mouse)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsDeshpande, I.S. / Liang, J. / Hedeen, D. / Roberts, K.J. / Zhang, Y. / Ha, B. / Latorraca, N.R. / Faust, B. / Dror, R.O. / Beachy, P.A. ...Deshpande, I.S. / Liang, J. / Hedeen, D. / Roberts, K.J. / Zhang, Y. / Ha, B. / Latorraca, N.R. / Faust, B. / Dror, R.O. / Beachy, P.A. / Myers, B.R. / Manglik, A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/Office of the DirectorDP5-OD023048-01 United States
CitationJournal: Nature / Year: 2019
Title: Smoothened stimulation by membrane sterols drives Hedgehog pathway activity.
Authors: Deshpande, I. / Liang, J. / Hedeen, D. / Roberts, K.J. / Zhang, Y. / Ha, B. / Latorraca, N.R. / Faust, B. / Dror, R.O. / Beachy, P.A. / Myers, B.R. / Manglik, A.
History
DepositionFeb 26, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 3, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Jul 24, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _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_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_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 1.4Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Smoothened homolog
B: NbSmo8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,05115
Polymers73,0222
Non-polymers4,02913
Water543
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5170 Å2
ΔGint-25 kcal/mol
Surface area27440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.010, 121.090, 157.010
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number17
Space group name H-MP2221
Space group name HallP2c2

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Components

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Protein / Antibody / Sugars , 3 types, 4 molecules AB

#1: Protein Smoothened homolog / SMO


Mass: 58788.301 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Smo, Smoh / Plasmid: pVLAD6 / Cell line (production host): HEK293 GNTI- / Production host: Homo sapiens (human) / References: UniProt: P56726
#2: Antibody NbSmo8


Mass: 14233.714 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Lama glama (llama)
#6: 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.: 2 / 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 , 6 types, 14 molecules

#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical
ChemComp-OLB / (2S)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate


Mass: 356.540 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Formula: C21H40O4
#7: Chemical ChemComp-LKD / 3-chloro-4,7-difluoro-N-{[2-methoxy-5-(pyridin-4-yl)phenyl]methyl}-N-[trans-4-(methylamino)cyclohexyl]-1-benzothiophene-2-carboxamide


Mass: 556.066 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H28ClF2N3O2S
#8: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.73 Å3/Da / Density % sol: 54.88 % / Description: Small 2x5x10 micron blades
Crystal growTemperature: 293.15 K / Method: lipidic cubic phase
Details: 0.1 M MES pH 6.0, 0.1 M ammonium phosphate dibasic, 1.5% 1,2,3-Heptanetriol, 22% PEG 300

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Data collection

DiffractionMean temperature: 293.15 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.033 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 18464 / % possible obs: 96.2 % / Redundancy: 6.63 % / Biso Wilson estimate: 81.36 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.27 / Net I/σ(I): 5.48
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 3.5 % / Rmerge(I) obs: 1.87 / Mean I/σ(I) obs: 0.92 / Num. unique obs: 1732 / CC1/2: 0.23 / % possible all: 94

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Processing

Software
NameVersionClassification
BUSTERrefinement
PHENIX1.12_2829refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5L7D, 3P0G

5l7d

3p0g


Resolution: 2.8→47.94 Å / SU ML: 0.526 / Cross valid method: FREE R-VALUE / σ(F): 1.336 / Phase error: 34.4
RfactorNum. reflection% reflection
Rfree0.2944 926 5 %
Rwork0.2454 --
obs0.248 18441 96.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 74.4 Å2
Refinement stepCycle: LAST / Resolution: 2.8→47.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4648 0 251 3 4902
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00839569966065043
X-RAY DIFFRACTIONf_angle_d0.5794431000516865
X-RAY DIFFRACTIONf_chiral_restr0.0419250752502757
X-RAY DIFFRACTIONf_plane_restr0.00247926809185848
X-RAY DIFFRACTIONf_dihedral_angle_d19.81319301421871
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8001-2.94770.37251250.35852382X-RAY DIFFRACTION94.2481203008
2.9477-3.13230.37471280.332383X-RAY DIFFRACTION94.1154422789
3.1323-3.37410.38421340.28262499X-RAY DIFFRACTION97.7720014853
3.3741-3.71350.32571320.26722514X-RAY DIFFRACTION97.9274611399
3.7135-4.25060.3241340.22622542X-RAY DIFFRACTION97.4508375819
4.2506-5.35420.27381340.21292538X-RAY DIFFRACTION96.7765302427
5.3542-47.95020.23911390.23522657X-RAY DIFFRACTION95.3615279673

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