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- PDB-5l7i: Structure of human Smoothened in complex with Vismodegib -

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Basic information

Entry
Database: PDB / ID: 5l7i
TitleStructure of human Smoothened in complex with Vismodegib
ComponentsSmoothened homolog,Soluble cytochrome b562,Smoothened homolog
KeywordsMEMBRANE PROTEIN / G protein coupled receptor / morphogen signaling / hedgehog signaling / signaling protein
Function / homology
Function and homology information


ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / regulation of heart morphogenesis / negative regulation of hair follicle development / 9+0 non-motile cilium / central nervous system neuron differentiation / regulation of somatic stem cell population maintenance / pancreas morphogenesis / epithelial-mesenchymal cell signaling / : ...ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / regulation of heart morphogenesis / negative regulation of hair follicle development / 9+0 non-motile cilium / central nervous system neuron differentiation / regulation of somatic stem cell population maintenance / pancreas morphogenesis / epithelial-mesenchymal cell signaling / : / myoblast migration / atrial septum morphogenesis / contact inhibition / determination of left/right asymmetry in lateral mesoderm / spinal cord dorsal/ventral patterning / left/right axis specification / ciliary tip / Activation of SMO / patched binding / thalamus development / somite development / positive regulation of branching involved in ureteric bud morphogenesis / type B pancreatic cell development / dorsal/ventral neural tube patterning / forebrain morphogenesis / cellular response to cholesterol / BBSome-mediated cargo-targeting to cilium / positive regulation of organ growth / smooth muscle tissue development / pattern specification process / cerebellar cortex morphogenesis / mammary gland epithelial cell differentiation / dentate gyrus development / commissural neuron axon guidance / positive regulation of multicellular organism growth / dopaminergic neuron differentiation / oxysterol binding / 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 / ciliary membrane / positive regulation of mesenchymal cell proliferation / anterior/posterior pattern specification / 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 / protein kinase A catalytic subunit binding / neuroblast proliferation / endoplasmic reticulum-Golgi intermediate compartment / vasculogenesis / Hedgehog 'off' state / skeletal muscle fiber development / homeostasis of number of cells within a tissue / centriole / protein sequestering activity / negative regulation of protein phosphorylation / epithelial cell proliferation / central nervous system development / positive regulation of epithelial cell proliferation / astrocyte activation / G protein-coupled receptor activity / Hedgehog 'on' state / multicellular organism growth / cilium / cerebral cortex development / osteoblast differentiation / positive regulation of protein import into nucleus / protein import into nucleus / endocytic vesicle membrane / late endosome / gene expression / in utero embryonic development / electron transfer activity / periplasmic space / protein stabilization / positive regulation of cell migration / iron ion binding / negative regulation of gene expression / intracellular membrane-bounded organelle / dendrite / apoptotic process / heme binding / positive regulation of gene expression / negative regulation of apoptotic process / Golgi apparatus / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / extracellular exosome / plasma membrane
Similarity search - Function
Frizzled cysteine-rich domain / Frizzled cysteine-rich 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 / Frizzled cysteine-rich 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. / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Up-down Bundle / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-MPG / Chem-VIS / Soluble cytochrome b562 / Protein smoothened
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsByrne, E.X.B. / Sircar, R. / Miller, P.S. / Hedger, G. / Luchetti, G. / Nachtergaele, S. / Tully, M.D. / Mydock-McGrane, L. / Covey, D.F. / Rambo, R.F. ...Byrne, E.X.B. / Sircar, R. / Miller, P.S. / Hedger, G. / Luchetti, G. / Nachtergaele, S. / Tully, M.D. / Mydock-McGrane, L. / Covey, D.F. / Rambo, R.F. / Sansom, M.S.P. / Newstead, S. / Rohatgi, R. / Siebold, C.
CitationJournal: Nature / Year: 2016
Title: Structural basis of Smoothened regulation by its extracellular domains.
Authors: Byrne, E.F. / Sircar, R. / Miller, P.S. / Hedger, G. / Luchetti, G. / Nachtergaele, S. / Tully, M.D. / Mydock-McGrane, L. / Covey, D.F. / Rambo, R.P. / Sansom, M.S. / Newstead, S. / Rohatgi, R. / Siebold, C.
History
DepositionJun 3, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 20, 2016Provider: repository / Type: Initial release
Revision 1.1Jul 27, 2016Group: Structure summary
Revision 1.2Aug 3, 2016Group: Database references
Revision 1.3Aug 10, 2016Group: Database references
Revision 1.4Jul 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.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5Jan 10, 2024Group: 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,Soluble cytochrome b562,Smoothened homolog
B: Smoothened homolog,Soluble cytochrome b562,Smoothened homolog
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,3688
Polymers141,5682
Non-polymers1,8006
Water0
1
A: Smoothened homolog,Soluble cytochrome b562,Smoothened homolog
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,4263
Polymers70,7841
Non-polymers6432
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Smoothened homolog,Soluble cytochrome b562,Smoothened homolog
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,9415
Polymers70,7841
Non-polymers1,1574
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)52.820, 71.290, 107.020
Angle α, β, γ (deg.)91.53, 98.20, 105.92
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 70783.969 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Human
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: SMO, SMOH, cybC / Plasmid: pHLsec / Cell line (production host): HEK-293S-GnTI- / Production host: Homo sapiens (human) / References: UniProt: Q99835, UniProt: P0ABE7
#2: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
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
#3: Chemical ChemComp-VIS / 2-chloranyl-~{N}-(4-chloranyl-3-pyridin-2-yl-phenyl)-4-methylsulfonyl-benzamide / Vismodegib


Mass: 421.297 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H14Cl2N2O3S / Comment: medication*YM
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-MPG / [(Z)-octadec-9-enyl] (2R)-2,3-bis(oxidanyl)propanoate


Mass: 356.540 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H40O4

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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: 2.7 Å3/Da / Density % sol: 54.49 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase / pH: 4
Details: 0.09 M sodium acetate pH4, 0.09 M sodium malonate, 27% (v/v) PEG500 DME, 0.1 M sodium acetate, 0.5 mM zinc chloride, 0.1 M ammonium fluoride.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9686 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 5, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 3.3→68 Å / Num. obs: 21097 / % possible obs: 94.7 % / Redundancy: 1.8 % / Biso Wilson estimate: 63.36 Å2 / CC1/2: 0.953 / Rmerge(I) obs: 0.152 / Net I/σ(I): 3.7
Reflection shellResolution: 3.3→3.39 Å / Redundancy: 1.7 % / Mean I/σ(I) obs: 0.6 / % possible all: 85.8

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4qim

4qim


Resolution: 3.3→59.32 Å / Cor.coef. Fo:Fc: 0.8907 / Cor.coef. Fo:Fc free: 0.8726 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.537
RfactorNum. reflection% reflectionSelection details
Rfree0.2567 1013 4.92 %RANDOM
Rwork0.2448 ---
obs0.2454 20588 94.55 %-
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--16.8545 Å2-24.5219 Å2-10.164 Å2
2---4.8895 Å2-7.5493 Å2
3---21.744 Å2
Refine analyzeLuzzati coordinate error obs: 0.655 Å
Refinement stepCycle: 1 / Resolution: 3.3→59.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8988 0 119 0 9107
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0089355HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.8712715HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4222SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes197HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1411HARMONIC5
X-RAY DIFFRACTIONt_it9355HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.02
X-RAY DIFFRACTIONt_other_torsion3.03
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1192SEMIHARMONIC5
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_contact10593SEMIHARMONIC4
LS refinement shellResolution: 3.3→3.48 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2696 105 4.28 %
Rwork0.2876 2349 -
all0.2868 2454 -
obs--89.94 %
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)
14.5869-1.22741.89084.6946-1.57446.9616-0.0276-0.02550.0610.05190.01660.0882-0.0229-0.11830.0110.17260.1622-0.1790.3432-0.1361-0.38518.770342.28133.2967
20.8875-0.3440.23920.32730.65521.64290.0016-0.0032-0.03620.00990.00590.0012-0.01260.0243-0.00750.09590.0093-0.05860.0020.06070.01749.003644.3417-20.622
31.4472-0.29370.7061.3633-0.56334.8458-0.12030.21640.23840.0543-0.0577-0.0163-0.32870.25920.1780.14540.0119-0.1475-0.0190.1041-0.09853.252.9703-52.1604
43.3516-0.03232.24370.6298-0.72643.6330.02570.0342-0.0434-0.047-0.0183-0.06520.00480.0508-0.00730.1045-0.10880.03190.03460.168-0.057510.323982.4286-100.9578
55.86140.4741-2.19964.983-2.66636.91590.0496-0.10310.0645-0.0534-0.18390.1355-0.0464-0.11270.13430.17430.0215-0.1070.2695-0.0025-0.29727.466428.8486-116.6565
6-0.05580.3356-0.23030.3751-0.44511.2302-0.01110.0480.0091-0.0122-0.0123-0.00040.00690.01480.02340.060.00080.00030.1540.0077-0.059-1.654327.0712-92.5812
71.4290.1732-0.48021.8621-1.01046.4071-0.2830.1691-0.10420.12160.15830.11320.3633-0.1410.1247-0.0005-0.07870.0753-0.0444-0.0039-0.0471-5.113118.7272-59.7741
84.3952-2.2009-2.36331.12791.77275.46980.00230.0212-0.04710.04190.019-0.01510.0103-0.0371-0.02130.2328-0.0468-0.0229-0.14480.1035-0.04688.1902-11.174-13.5834
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|57 - A|190 }
2X-RAY DIFFRACTION2{ A|191 - A|216 }
3X-RAY DIFFRACTION3{ A|217 - A|551 }
4X-RAY DIFFRACTION4{ A|1011 - A|1131 }
5X-RAY DIFFRACTION5{ B|58 - B|190 }
6X-RAY DIFFRACTION6{ B|191 - B|216 }
7X-RAY DIFFRACTION7{ B|217 - B|552 }
8X-RAY DIFFRACTION8{ B|1011 - B|1131 }

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