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- PDB-4n4w: Structure of the human smoothened receptor in complex with SANT-1. -

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Basic information

Entry
Database: PDB / ID: 4n4w
TitleStructure of the human smoothened receptor in complex with SANT-1.
ComponentsCytochrome b(562),Smoothened homolog
KeywordsMembrane Protein / Transport Protein / Human smoothened receptor / antitumor agent / novel protein engineering / GPCR network / PSI-Biology / Structural Genomics / GPCR / membrane
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 / central nervous system neuron differentiation / 9+0 non-motile cilium / pancreas morphogenesis / regulation of somatic stem cell population maintenance ...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 / central nervous system neuron differentiation / 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 / ciliary tip / Activation of SMO / patched binding / forebrain morphogenesis / 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 / positive regulation of branching involved in ureteric bud morphogenesis / cellular response to cholesterol / thalamus development / cerebellar cortex morphogenesis / pattern specification process / mammary gland epithelial cell differentiation / dentate gyrus development / commissural neuron axon guidance / dopaminergic neuron differentiation / oxysterol binding / positive regulation of multicellular organism growth / positive regulation of smoothened signaling pathway / Class B/2 (Secretin family receptors) / cell fate specification / neural crest cell migration / cAMP-dependent protein kinase inhibitor activity / negative regulation of DNA binding / anterior/posterior pattern specification / positive regulation of mesenchymal cell proliferation / ciliary membrane / hair follicle morphogenesis / midgut development / negative regulation of epithelial cell differentiation / smoothened signaling pathway / positive regulation of neuroblast proliferation / endoplasmic reticulum-Golgi intermediate compartment / protein kinase A catalytic subunit binding / heart looping / odontogenesis of dentin-containing tooth / negative regulation of protein phosphorylation / neuroblast proliferation / vasculogenesis / Hedgehog 'off' state / skeletal muscle fiber development / homeostasis of number of cells within a tissue / centriole / protein sequestering activity / positive regulation of epithelial cell proliferation / central nervous system development / epithelial cell proliferation / astrocyte activation / electron transport chain / Hedgehog 'on' state / G protein-coupled receptor activity / multicellular organism growth / cerebral cortex development / positive regulation of protein import into nucleus / protein import into nucleus / osteoblast differentiation / endocytic vesicle membrane / late endosome / gene expression / in utero embryonic development / 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 / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / 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. / Cytochrome c/b562 / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Four Helix Bundle (Hemerythrin (Met), subunit A) / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / DI(HYDROXYETHYL)ETHER / Chem-SNT / Soluble cytochrome b562 / Protein smoothened
Similarity search - Component
Biological speciesShigella flexneri 5 str. 8401 (bacteria)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsWang, C. / Wu, H. / Han, G.W. / Cherezov, V. / Stevens, R.C. / GPCR Network (GPCR)
CitationJournal: Nat Commun / Year: 2014
Title: Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs.
Authors: Wang, C. / Wu, H. / Evron, T. / Vardy, E. / Han, G.W. / Huang, X.P. / Hufeisen, S.J. / Mangano, T.J. / Urban, D.J. / Katritch, V. / Cherezov, V. / Caron, M.G. / Roth, B.L. / Stevens, R.C.
History
DepositionOct 8, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2014Group: Database references
Revision 1.2Jun 7, 2017Group: Database references / Structure summary
Revision 1.3Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / 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 / pdbx_struct_special_symmetry / pdbx_unobs_or_zero_occ_atoms / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_special_symmetry.label_asym_id / _pdbx_unobs_or_zero_occ_atoms.auth_asym_id / _pdbx_unobs_or_zero_occ_atoms.auth_seq_id / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Sep 20, 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
Revision 2.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome b(562),Smoothened homolog
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,3879
Polymers53,1211
Non-polymers2,2668
Water1448
1
A: Cytochrome b(562),Smoothened homolog
hetero molecules

A: Cytochrome b(562),Smoothened homolog
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,77518
Polymers106,2422
Non-polymers4,53316
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_554-x,y,-z-1/21
Buried area4420 Å2
ΔGint-84 kcal/mol
Surface area46260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.640, 110.880, 145.210
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-606-

ZN

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Components

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein Cytochrome b(562),Smoothened homolog / SMO / Protein Gx


Mass: 53121.004 Da / Num. of mol.: 1 / Fragment: Residues 190-555 / Mutation: M29W, H124I, R128L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Shigella flexneri 5 str. 8401 (bacteria), (gene. exp.) Homo sapiens (human)
Strain: 8401 / Gene: cybC, SFV_4255, SMO, SMOH / Plasmid: pFASTBAC / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): sf9 / References: UniProt: Q0SXH8, UniProt: Q99835
#2: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE

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Non-polymers , 6 types, 15 molecules

#3: Chemical ChemComp-SNT / (E)-N-(4-benzylpiperazin-1-yl)-1-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methanimine / SANT-1


Mass: 373.494 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27N5
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H40O4
#6: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#7: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 4

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Sample preparation

CrystalDensity Matthews: 3.21 Å3/Da / Density % sol: 61.64 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase / pH: 6.9
Details: NH4F 150mM, HEPES PH 6.9 100mM, PEG 400 27%, Jeffamine 2.5%, Lipidic Cubic Phase (LCP), temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.033 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Dec 1, 2012 / Details: mirrors
RadiationMonochromator: double crystal / Protocol: 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: 16010 / % possible obs: 94.5 % / Redundancy: 4.2 % / Biso Wilson estimate: 77.7 Å2 / Rmerge(I) obs: 0.12 / Net I/σ(I): 11.8
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.641 / Mean I/σ(I) obs: 1.4 / Num. unique all: 1526 / % possible all: 92.3

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Processing

Software
NameVersionClassification
Blu-IceIcedata collection
PHASERphasing
BUSTER2.10.0refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4JKV

4jkv


Resolution: 2.8→49.35 Å / Cor.coef. Fo:Fc: 0.9342 / Cor.coef. Fo:Fc free: 0.9077 / SU R Cruickshank DPI: 1.046 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2533 776 4.85 %RANDOM
Rwork0.2044 ---
obs0.2066 15986 93.05 %-
Displacement parametersBiso mean: 81.12 Å2
Baniso -1Baniso -2Baniso -3
1--6.512 Å20 Å20 Å2
2---6.4401 Å20 Å2
3---12.9521 Å2
Refine analyzeLuzzati coordinate error obs: 0.415 Å
Refinement stepCycle: LAST / Resolution: 2.8→49.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3551 0 129 8 3688
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013794HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.085157HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1697SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes75HARMONIC2
X-RAY DIFFRACTIONt_gen_planes547HARMONIC5
X-RAY DIFFRACTIONt_it3794HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.54
X-RAY DIFFRACTIONt_other_torsion3.45
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion498SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4652SEMIHARMONIC4
LS refinement shellResolution: 2.8→2.99 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.3188 144 5.54 %
Rwork0.2191 2454 -
all0.2243 2598 -
obs--93.05 %
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)
14.942.4672-0.12018.2003-2.1124.01180.13030.1285-0.2445-0.2352-0.0555-0.03480.338-0.2673-0.0748-0.03830.0029-0.095-0.0304-0.0208-0.2776-12.2216-50.7429-37.6558
21.09470.14220.12940.71570.87696.1582-0.07620.07170.0287-0.14740.04420.0748-0.35110.39770.032-0.15880.01040.05820.08440.0453-0.304-14.7527-23.2528-4.8813
30-0.1413-0.15560-0.73410-0.0038-0.00370.0020.0092-0.02080.00430.00020.00170.0247-0.0247-0.04430.06090.04130.0437-0.0171-30.409-20.6131-44.7856
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|-2 - 106 }A-2 - 106
2X-RAY DIFFRACTION2{ A|190 - 553 }A190 - 553
3X-RAY DIFFRACTION3{ A|601 - 604 }A601 - 604

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