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- PDB-8dvm: Crystal structure of LRP6 E3E4 in complex with disulfide constrai... -

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Basic information

Entry
Database: PDB / ID: 8dvm
TitleCrystal structure of LRP6 E3E4 in complex with disulfide constrained peptide E3.6
Components
  • E3.6 Disulfide constrained peptide
  • Low-density lipoprotein receptor-related protein 6
KeywordsSIGNALING PROTEIN / LRP6 / E3E4 / Wnt Signaling / Disulfide constrained peptide / Wnt agonism
Function / homology
Function and homology information


Wnt-Frizzled-LRP5/6 complex / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / neural crest formation / Signaling by RNF43 mutants / negative regulation of protein serine/threonine kinase activity / 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 / neural crest formation / Signaling by RNF43 mutants / negative regulation of protein serine/threonine kinase activity / kinase inhibitor activity / toxin transmembrane transporter activity / Wnt receptor activity / low-density lipoprotein particle receptor activity / Wnt-protein binding / midbrain dopaminergic neuron differentiation / cellular response to cholesterol / dopaminergic neuron differentiation / frizzled binding / Wnt signalosome / Disassembly of the destruction complex and recruitment of AXIN to the membrane / neural crest cell differentiation / negative regulation of smooth muscle cell apoptotic process / canonical Wnt signaling pathway / coreceptor activity / positive regulation of cell cycle / Regulation of FZD by ubiquitination / positive regulation of DNA-binding transcription factor activity / protein localization to plasma membrane / TCF dependent signaling in response to WNT / cell-cell adhesion / response to peptide hormone / Wnt signaling pathway / endocytosis / nervous system development / positive regulation of cytosolic calcium ion concentration / early endosome membrane / cytoplasmic vesicle / chemical synaptic transmission / membrane raft / signaling receptor binding / neuronal cell body / synapse / positive regulation of DNA-templated transcription / cell surface / endoplasmic reticulum / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular region / identical protein binding / plasma membrane
Similarity search - Function
Low density lipoprotein receptor-related protein 5/6 / : / 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-related protein 5/6 / : / 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 / 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
Low-density lipoprotein receptor-related protein 6
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsThakur, A.K. / Liau, N.P.D. / Sudhamsu, J. / Hannoush, R.N.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Acs Chem.Biol. / Year: 2023
Title: Synthetic Multivalent Disulfide-Constrained Peptide Agonists Potentiate Wnt1/ beta-Catenin Signaling via LRP6 Coreceptor Clustering.
Authors: Thakur, A.K. / Miller, S.E. / Liau, N.P.D. / Hwang, S. / Hansen, S. / de Sousa E Melo, F. / Sudhamsu, J. / Hannoush, R.N.
History
DepositionJul 29, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1May 3, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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: E3.6 Disulfide constrained peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,29825
Polymers75,2452
Non-polymers4,05323
Water4,035224
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8580 Å2
ΔGint55 kcal/mol
Surface area26960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.462, 102.978, 108.775
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

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


Mass: 71774.625 Da / Num. of mol.: 1
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/peptide E3.6 Disulfide constrained peptide


Mass: 3470.059 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Sugars , 4 types, 5 molecules

#3: Polysaccharide alpha-L-fucopyranose-(1-3)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-L-fucopyranose-(1-3)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-3)][alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1212.157 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-3[LFucpa1-6]DGlcpNAcb1-4DGlcpNAcb1-4[LFucpa1-3][LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2-1-1-2-2-2/a3-b1_a4-c1_a6-g1_c4-d1_d3-e1_d6-f1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(3+1)][a-L-Fucp]{}[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(3+1)][a-L-Fucp]{}[(6+1)][a-L-Fucp]{}}}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#4: 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#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.: 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

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Non-polymers , 4 types, 242 molecules

#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#8: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 14
Source method: isolated from a genetically manipulated source
Formula: C2H6O2
#9: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C6H13NO4S / Comment: pH buffer*YM
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 224 / Source method: isolated from a natural source / Formula: H2O

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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: 2.61 Å3/Da / Density % sol: 50.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.3 / Details: 100 mM MES pH 6.3, 12% PEG 20K

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jun 30, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 2→46.54 Å / Num. obs: 50517 / % possible obs: 98.71 % / Redundancy: 6.7 % / Biso Wilson estimate: 38.18 Å2 / CC1/2: 0.999 / Net I/σ(I): 15.68
Reflection shellResolution: 2→2.072 Å / Redundancy: 6.7 % / Num. unique obs: 4407 / CC1/2: 0.451 / CC star: 0.788 / % possible all: 87.33

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Processing

Software
NameVersionClassification
PHENIX1.20rc3-4406_finalrefinement
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4A0P

4a0p


Resolution: 2→46.54 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 25.65 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2205 5911 6.15 %
Rwork0.1857 90168 -
obs0.1879 50517 98.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 150.48 Å2 / Biso mean: 49.3589 Å2 / Biso min: 22.23 Å2
Refinement stepCycle: final / Resolution: 2→46.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5013 0 262 224 5499
Biso mean--73.08 47.48 -
Num. residues----627
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2-2.020.3795830.3428149748
2.02-2.040.35652150.32192986100
2.04-2.070.31511880.30583055100
2.07-2.090.33751930.29933076100
2.09-2.120.35912230.29353017100
2.12-2.150.30931920.2853103100
2.15-2.180.33532230.2773013100
2.18-2.210.33561890.27413063100
2.21-2.250.30151710.25543085100
2.25-2.290.29762260.26023038100
2.29-2.330.27191990.24363050100
2.33-2.370.29051860.2263107100
2.37-2.410.28032020.23323089100
2.41-2.460.25811950.21713023100
2.46-2.520.29242070.21383057100
2.52-2.570.31172020.21493063100
2.57-2.640.25041980.21153073100
2.64-2.710.25432010.2123071100
2.71-2.790.28321980.2063061100
2.79-2.880.2862130.20343043100
2.88-2.980.23121870.19973064100
2.98-3.10.24262040.18833049100
3.1-3.240.22552030.19313070100
3.24-3.410.22662090.18393051100
3.41-3.630.19612090.16013048100
3.63-3.910.16531860.15393090100
3.91-4.30.15792150.14313044100
4.3-4.920.1682130.1223047100
4.92-6.20.18451860.15513076100
6.2-46.540.15591950.16363059100
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)
11.9063-0.56980.29831.44750.25343.1860.05740.10180.0963-0.13840.0142-0.0394-0.1173-0.1181-0.06450.29380.0389-0.03650.2581-0.02670.3395-29.4192-8.39543.7179
21.9409-0.21530.31091.3692-0.03892.1461-0.0949-0.02360.00480.10980.0905-0.1145-0.08540.01710.00290.24970.0084-0.0170.2745-0.0490.2279-7.6169-30.908135.8375
35.78665.451-4.74725.7109-5.64857.4814-0.73782.083-0.7387-2.59120.5775-0.70851.5110.11370.2231.14180.0814-0.040.8282-0.15290.8546-20.9399-24.7633-5.6961
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 630 through 920 )A630 - 920
2X-RAY DIFFRACTION2chain 'A' and (resid 921 through 1247 )A921 - 1247
3X-RAY DIFFRACTION3chain 'B' and (resid 1 through 30 )B1 - 30

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