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- PDB-6l6r: Crystal structure of LRP6 E1E2-SOST complex -

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Basic information

Entry
Database: PDB / ID: 6l6r
TitleCrystal structure of LRP6 E1E2-SOST complex
Components
  • Low-density lipoprotein receptor-related protein 6
  • Sclerostin
KeywordsSIGNALING PROTEIN / LRP6 / Sclerostin / Wnt signaling / inhibitor
Function / homology
Function and homology information


Wnt-Frizzled-LRP5/6 complex / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / Signaling by RNF43 mutants / neural crest formation / BMP binding / kinase inhibitor activity / toxin transmembrane transporter activity / Wnt receptor activity / low-density lipoprotein particle receptor activity / Wnt-protein binding ...Wnt-Frizzled-LRP5/6 complex / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / Signaling by RNF43 mutants / neural crest formation / BMP binding / kinase inhibitor activity / toxin transmembrane transporter activity / Wnt receptor activity / low-density lipoprotein particle receptor activity / Wnt-protein binding / cellular response to cholesterol / midbrain dopaminergic neuron differentiation / negative regulation of protein serine/threonine kinase activity / dopaminergic neuron differentiation / frizzled binding / negative regulation of ossification / Wnt signalosome / neural crest cell differentiation / cellular response to parathyroid hormone stimulus / Disassembly of the destruction complex and recruitment of AXIN to the membrane / molecular function inhibitor activity / negative regulation of Wnt signaling pathway / negative regulation of smooth muscle cell apoptotic process / negative regulation of BMP signaling pathway / canonical Wnt signaling pathway / negative regulation of protein-containing complex assembly / BMP signaling pathway / coreceptor activity / positive regulation of cell cycle / response to mechanical stimulus / Regulation of FZD by ubiquitination / ossification / TCF dependent signaling in response to WNT / protein localization to plasma membrane / negative regulation of canonical Wnt signaling pathway / Wnt signaling pathway / response to peptide hormone / cell-cell adhesion / positive regulation of DNA-binding transcription factor activity / endocytosis / nervous system development / heparin binding / positive regulation of cytosolic calcium ion concentration / early endosome membrane / cytoplasmic vesicle / carbohydrate binding / chemical synaptic transmission / DNA-binding transcription factor binding / membrane raft / signaling receptor binding / neuronal cell body / synapse / positive regulation of DNA-templated transcription / Golgi apparatus / cell surface / endoplasmic reticulum / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / protein-containing complex / extracellular space / extracellular region / identical protein binding / plasma membrane
Similarity search - Function
Sclerostin/Sclerostin domain-containing protein 1 / Sclerostin (SOST) / Low density lipoprotein receptor-related protein 5/6 / : / Cystine knot, C-terminal / C-terminal cystine knot-like domain (CTCK) / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain ...Sclerostin/Sclerostin domain-containing protein 1 / Sclerostin (SOST) / Low density lipoprotein receptor-related protein 5/6 / : / Cystine knot, C-terminal / C-terminal cystine knot-like domain (CTCK) / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Cystine-knot cytokine / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Six-bladed beta-propeller, TolB-like / Coagulation Factor Xa inhibitory site / Epidermal growth factor-like domain. / EGF-like domain signature 2. / EGF-like domain
Similarity search - Domain/homology
ACETATE ION / Low-density lipoprotein receptor-related protein 6 / Sclerostin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.8 Å
AuthorsChoi, H.-J. / Kim, J.
Funding support Korea, Republic Of, 2items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)NRF-2016R1A2B4013488 Korea, Republic Of
National Research Foundation (NRF, Korea)NRF-2019M3E5D6063903 Korea, Republic Of
CitationJournal: Nat Commun / Year: 2020
Title: Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains.
Authors: Kim, J. / Han, W. / Park, T. / Kim, E.J. / Bang, I. / Lee, H.S. / Jeong, Y. / Roh, K. / Kim, J. / Kim, J.S. / Kang, C. / Seok, C. / Han, J.-K. / Choi, H.-J.
History
DepositionOct 29, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 28, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Low-density lipoprotein receptor-related protein 6
B: Low-density lipoprotein receptor-related protein 6
C: Sclerostin
D: Sclerostin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)179,36215
Polymers176,8884
Non-polymers2,47411
Water00
1
A: Low-density lipoprotein receptor-related protein 6
C: Sclerostin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,7118
Polymers88,4442
Non-polymers1,2676
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Low-density lipoprotein receptor-related protein 6
D: Sclerostin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,6527
Polymers88,4442
Non-polymers1,2085
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)252.792, 252.792, 86.286
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number172
Space group name H-MP64
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and resid 20 through 630)
21(chain B and resid 20 through 630)
12(chain C and (resid 78 through 121 or resid 131 through 177))
22chain D

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111ASPASPPROPRO(chain A and resid 20 through 630)AA20 - 6302 - 612
211ASPASPPROPRO(chain B and resid 20 through 630)BB20 - 6302 - 612
112TYRTYRARGARG(chain C and (resid 78 through 121 or resid 131 through 177))CC78 - 12159 - 102
122ASPASPSERSER(chain C and (resid 78 through 121 or resid 131 through 177))CC131 - 177112 - 158
212TYRTYRSERSERchain DDD78 - 17759 - 158

NCS ensembles :
ID
1
2

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Components

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Protein , 2 types, 4 molecules ABCD

#1: Protein Low-density lipoprotein receptor-related protein 6 / LRP-6


Mass: 70531.461 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LRP6 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: O75581
#2: Protein Sclerostin


Mass: 17912.359 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOST, UNQ2976/PRO7455/PRO7476 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9BQB4

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Sugars , 3 types, 6 molecules

#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: Polysaccharide alpha-L-fucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 513.490 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-4[LFucpa1-6]DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-L-Fucp]{}[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#5: 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: 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

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Non-polymers , 2 types, 5 molecules

#6: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#7: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2

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Details

Has ligand of interestN

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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: 4.5 Å3/Da / Density % sol: 72.66 %
Crystal growTemperature: 301 K / Method: vapor diffusion, hanging drop / Details: PEG 8000, magnesium acetate, sodium citrate, HEPES

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.03314 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Oct 13, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03314 Å / Relative weight: 1
ReflectionResolution: 3.8→29.861 Å / Num. obs: 31260 / % possible obs: 99.6 % / Redundancy: 4.3 % / Biso Wilson estimate: 87.19 Å2 / CC1/2: 0.98 / Rmerge(I) obs: 0.2 / Rpim(I) all: 0.12 / Rrim(I) all: 0.253 / Net I/σ(I): 6.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
3.8-4.014.30.7545170.7910.4070.86199.5
12.02-29.8640.0619790.9950.0340.07193.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIXv1.16refinement
XDSdata reduction
Aimless0.5.28data scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1DOW, 2K8P

1dow

2k8p


Resolution: 3.8→29.861 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 25.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2564 2465 7.89 %
Rwork0.2069 28795 -
obs0.2108 31260 99.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 189.44 Å2 / Biso mean: 100.5119 Å2 / Biso min: 61.89 Å2
Refinement stepCycle: final / Resolution: 3.8→29.861 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11154 0 160 0 11314
Biso mean--129.06 --
Num. residues----1404
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00311599
X-RAY DIFFRACTIONf_angle_d0.72615792
X-RAY DIFFRACTIONf_chiral_restr0.0491759
X-RAY DIFFRACTIONf_plane_restr0.0042027
X-RAY DIFFRACTIONf_dihedral_angle_d12.7196943
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A5821X-RAY DIFFRACTION6.424TORSIONAL
12B5821X-RAY DIFFRACTION6.424TORSIONAL
21C901X-RAY DIFFRACTION6.424TORSIONAL
22D901X-RAY DIFFRACTION6.424TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
3.8001-3.8730.33621430.2816156999
3.873-3.95190.31851240.27451600100
3.9519-4.03760.31741250.24131591100
4.0376-4.13130.28451300.23541603100
4.1313-4.23440.30871550.2231566100
4.2344-4.34850.25671130.21011619100
4.3485-4.47610.25651410.19961563100
4.4761-4.620.27421340.1921608100
4.62-4.78450.22491550.18281583100
4.7845-4.97530.24371460.17341568100
4.9753-5.20060.21691370.18521587100
5.2006-5.47320.25471190.19741633100
5.4732-5.81370.24761230.2161609100
5.8137-6.25880.25461290.21291610100
6.2588-6.88170.29311430.20981598100
6.8817-7.86150.24311820.20211597100
7.8615-9.84540.24391420.18321610100
9.8454-29.8610.20151240.2033168199
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)
11.8867-1.31470.12812.2233-0.05611.095-0.08730.1148-0.1178-0.07040.1456-0.31340.19480.128500.7795-0.13080.06830.8993-0.09060.830557.6884294.04310.4249
22.0954-1.80750.26452.2867-0.1230.50150.0372-0.1280.23170.106-0.02430.0169-0.0653-0.1107-00.7078-0.08350.05491.0113-0.05470.838828.6539325.6335-30.416
30.0684-0.0782-0.15440.24040.40010.47190.2785-0.1145-0.73290.103-0.2160.07840.4530.0533-01.06990.0139-0.05931.17540.10981.317286.0273319.982323.21
40.238-0.0015-0.43210.01210.01630.5258-0.11090.15070.0268-0.3980.21540.72530.0464-0.3607-01.04170.0215-0.04031.20970.06121.227656.7286351.9276-43.2391
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain 'A' and resid 19 through 1002)A19 - 1002
2X-RAY DIFFRACTION2(chain 'B' and resid 20 through 1002)B20 - 1002
3X-RAY DIFFRACTION3(chain 'C' and resid 78 through 177)C78 - 177
4X-RAY DIFFRACTION4(chain 'D' and resid 78 through 177)D78 - 177

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