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- PDB-7zi0: Structure of human Smoothened in complex with cholesterol and SAG -

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Basic information

Entry
Database: PDB / ID: 7zi0
TitleStructure of human Smoothened in complex with cholesterol and SAG
ComponentsSmoothened homolog,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / Class F G protein coupled receptor / Hedgehog signalling / oncoprotein / drug target / signal transduction / morphogen / cholesterol
Function / homology
Function and homology information


ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / response to inositol / regulation of heart morphogenesis / contact inhibition / negative regulation of hair follicle development / 9+0 non-motile cilium / pancreas morphogenesis / regulation of somatic stem cell population maintenance / epithelial-mesenchymal cell signaling ...ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / response to inositol / regulation of heart morphogenesis / contact inhibition / negative regulation of hair follicle development / 9+0 non-motile cilium / pancreas morphogenesis / regulation of somatic stem cell population maintenance / epithelial-mesenchymal cell signaling / myoblast migration / atrial septum morphogenesis / spinal cord dorsal/ventral patterning / determination of left/right asymmetry in lateral mesoderm / left/right axis specification / Activation of SMO / patched binding / forebrain morphogenesis / ciliary tip / type B pancreatic cell development / somite development / positive regulation of organ growth / dorsal/ventral neural tube patterning / BBSome-mediated cargo-targeting to cilium / smooth muscle tissue development / cerebellar cortex morphogenesis / positive regulation of branching involved in ureteric bud morphogenesis / cellular response to cholesterol / pattern specification process / mammary gland epithelial cell differentiation / dentate gyrus development / commissural neuron axon guidance / dopaminergic neuron differentiation / oxysterol binding / thalamus development / central nervous system neuron differentiation / positive regulation of multicellular organism growth / positive regulation of smoothened signaling pathway / Class B/2 (Secretin family receptors) / cell fate specification / cAMP-dependent protein kinase inhibitor activity / neural crest cell migration / negative regulation of DNA binding / anterior/posterior pattern specification / positive regulation of mesenchymal cell proliferation / ciliary membrane / hair follicle morphogenesis / midgut development / smoothened signaling pathway / negative regulation of epithelial cell differentiation / positive regulation of neuroblast proliferation / heart looping / protein kinase A catalytic subunit binding / endoplasmic reticulum-Golgi intermediate compartment / odontogenesis of dentin-containing tooth / negative regulation of protein phosphorylation / neuroblast proliferation / vasculogenesis / Hedgehog 'off' state / skeletal muscle fiber development / centriole / homeostasis of number of cells within a tissue / protein sequestering activity / positive regulation of epithelial cell proliferation / central nervous system development / epithelial cell proliferation / Hedgehog 'on' state / astrocyte activation / electron transport chain / G protein-coupled receptor activity / cerebral cortex development / positive regulation of protein import into nucleus / multicellular organism growth / endocytic vesicle membrane / protein import into nucleus / osteoblast differentiation / late endosome / in utero embryonic development / gene expression / periplasmic space / electron transfer activity / protein stabilization / cilium / positive regulation of cell migration / iron ion binding / negative regulation of gene expression / intracellular membrane-bounded organelle / apoptotic process / heme binding / dendrite / positive regulation of gene expression / negative regulation of apoptotic process / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / Golgi apparatus / positive regulation of transcription by RNA polymerase II / extracellular exosome / plasma membrane
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. / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562
Similarity search - Domain/homology
CHOLESTEROL / Chem-MPG / Chem-V0S / Soluble cytochrome b562 / Protein smoothened
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsByrne, E.F.X. / Woolley, R.E. / Ansell, B. / Sansom, M.S.P. / Newstead, S. / Siebold, C.
Funding support United Kingdom, European Union, 2items
OrganizationGrant numberCountry
Cancer Research UKC20724/A26752 United Kingdom
European Research Council (ERC)647278European Union
CitationJournal: Sci Adv / Year: 2022
Title: Patched 1 regulates Smoothened by controlling sterol binding to its extracellular cysteine-rich domain.
Authors: Kinnebrew, M. / Woolley, R.E. / Ansell, T.B. / Byrne, E.F.X. / Frigui, S. / Luchetti, G. / Sircar, R. / Nachtergaele, S. / Mydock-McGrane, L. / Krishnan, K. / Newstead, S. / Sansom, M.S.P. / ...Authors: Kinnebrew, M. / Woolley, R.E. / Ansell, T.B. / Byrne, E.F.X. / Frigui, S. / Luchetti, G. / Sircar, R. / Nachtergaele, S. / Mydock-McGrane, L. / Krishnan, K. / Newstead, S. / Sansom, M.S.P. / Covey, D.F. / Siebold, C. / Rohatgi, R.
History
DepositionApr 7, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 15, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Smoothened homolog,Soluble cytochrome b562
B: Smoothened homolog,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,94510
Polymers141,5682
Non-polymers2,3778
Water00
1
A: Smoothened homolog,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2847
Polymers70,7841
Non-polymers1,5006
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Smoothened homolog,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,6613
Polymers70,7841
Non-polymers8772
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)122.860, 63.150, 208.060
Angle α, β, γ (deg.)90.000, 96.290, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein / Sugars , 2 types, 3 molecules AB

#1: Protein Smoothened homolog,Soluble cytochrome b562 / SMO / Protein Gx / Cytochrome b-562


Mass: 70783.969 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Human Smoothened with cytochrome b562 (BRIL) inserted in a cytoplasmic loop.,Human Smoothened with cytochrome b562 (BRIL) inserted in a cytoplasmic loop.,Human Smoothened with cytochrome ...Details: Human Smoothened with cytochrome b562 (BRIL) inserted in a cytoplasmic loop.,Human Smoothened with cytochrome b562 (BRIL) inserted in a cytoplasmic loop.,Human Smoothened with cytochrome b562 (BRIL) inserted in a cytoplasmic loop.
Source: (gene. exp.) Homo sapiens (human) / Gene: SMO, SMOH, cybC / Cell line (production host): HEK293 cells / Production host: Homo sapiens (human) / References: UniProt: Q99835, UniProt: P0ABE7
#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.: 1 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
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 , 4 types, 7 molecules

#2: Chemical ChemComp-V0S / 3-chloro-N-[trans-4-(methylamino)cyclohexyl]-N-{[3-(pyridin-4-yl)phenyl]methyl}-1-benzothiophene-2-carboxamide


Mass: 490.059 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H28ClN3OS / Feature type: SUBJECT OF INVESTIGATION / Comment: agonist*YM
#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-MPG / [(Z)-octadec-9-enyl] (2R)-2,3-bis(oxidanyl)propanoate


Mass: 356.540 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H40O4 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.83 Å3/Da / Density % sol: 56.59 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase / pH: 6
Details: 0.1 M MES pH6.0, 0.09-0.12 M potassium formate, 24-27% (v/v) PEG500 DME, 0.5 mM zinc chloride, 0.1 M ammonium fluoride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9686 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 24, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 3→60.4 Å / Num. obs: 31218 / % possible obs: 97.1 % / Redundancy: 3.1 % / CC1/2: 0.992 / CC star: 0.998 / Rmerge(I) obs: 0.097 / Rpim(I) all: 0.082 / Net I/σ(I): 9.9
Reflection shellResolution: 3→3.08 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.797 / Mean I/σ(I) obs: 1 / Num. unique obs: 2012 / CC1/2: 0.363 / CC star: 0.73 / Rpim(I) all: 0.796 / % possible all: 87.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
PDB_EXTRACT3.27data extraction
DIALSv1.1.3data reduction
Aimless0.5.23data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5L7D

5l7d


Resolution: 3→60 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.907 / SU B: 64.946 / SU ML: 0.498 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.476 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2748 1480 4.7 %RANDOM
Rwork0.2309 ---
obs0.2331 29738 96.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 267.69 Å2 / Biso mean: 130.621 Å2 / Biso min: 62.32 Å2
Baniso -1Baniso -2Baniso -3
1--3.35 Å20 Å24.81 Å2
2--4.6 Å20 Å2
3----2.26 Å2
Refinement stepCycle: final / Resolution: 3→60 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9245 0 164 0 9409
Biso mean--120.74 --
Num. residues----1171
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0199674
X-RAY DIFFRACTIONr_bond_other_d0.0070.029148
X-RAY DIFFRACTIONr_angle_refined_deg1.6411.9513165
X-RAY DIFFRACTIONr_angle_other_deg1.4222.98820975
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8285.0171168
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.98723.082425
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.819151523
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.6241570
X-RAY DIFFRACTIONr_chiral_restr0.0850.21455
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02110822
X-RAY DIFFRACTIONr_gen_planes_other0.0060.022342
LS refinement shellResolution: 3→3.078 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.428 93 -
Rwork0.416 1909 -
all-2002 -
obs--86.89 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.32360.2292-2.31561.4045-1.22183.0807-0.3834-0.1339-0.2766-0.06020.1085-0.15230.0481-0.05740.2750.6410.0765-0.07070.3597-0.00710.5502-45.395-34.15107.375
26.2254-1.9895-2.12472.73370.38651.40860.19640.2093-0.7295-0.1049-0.4625-0.1924-0.6186-0.32390.26610.6344-0.0150.06061.243-0.00280.184822.744-16.776-5.185
33.42.3719-5.20082.9031-2.40779.17740.19860.39010.19690.40560.2207-0.00770.0155-0.5251-0.41940.60910.0768-0.07360.66590.04660.4825-40.27-22.60685.242
46.9592-2.675-1.45922.2022-3.156112.10020.20590.43290.3194-0.0652-0.057-0.1211-0.1135-0.4459-0.14890.6151-0.05010.1090.83790.10610.254213.12-6.76916.724
50.92010.2411-1.17210.0795-0.42094.16690.05310.28030.02530.05280.0695-0.0474-0.1432-0.4117-0.12250.66650.0501-0.00460.67170.08990.3497-29.079-19.78356.471
61.1831-0.151-1.13160.05380.17352.70050.06710.2936-0.12590.0661-0.0498-0.0471-0.3176-0.1146-0.01730.6639-0.07330.03780.8760.1870.25582.103-9.64247.599
74.2982-2.09860.16731.98250.50050.45010.12240.6233-0.4427-0.2815-0.17630.2317-0.213-0.11190.05390.63350.09950.24481.126-0.16460.2820.851-38.86413.971
83.16382.265-1.8352.5789-2.17112.23780.06750.4216-0.1330.31480.0033-0.0385-0.07050.0046-0.07090.6733-0.076-0.07380.40150.00080.5112-12.805-39.52289.762
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A58 - 190
2X-RAY DIFFRACTION2B58 - 190
3X-RAY DIFFRACTION3A191 - 216
4X-RAY DIFFRACTION4B191 - 216
5X-RAY DIFFRACTION5A217 - 425
6X-RAY DIFFRACTION5A551 - 657
7X-RAY DIFFRACTION6B217 - 425
8X-RAY DIFFRACTION6B551 - 655
9X-RAY DIFFRACTION7A426 - 550
10X-RAY DIFFRACTION8B426 - 550

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