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- PDB-8bwl: Crystal structure of human Twisted gastrulation protein homolog 1... -

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Basic information

Entry
Database: PDB / ID: 8bwl
TitleCrystal structure of human Twisted gastrulation protein homolog 1 (TWSG1) in complex with human Growth Differentiation factor 5 (GDF5) and calcium
Components
  • Growth/differentiation factor 5
  • Twisted gastrulation protein homolog 1
KeywordsSIGNALING PROTEIN / Twisted gastrulation protein homolog 1 (TWSG1) / Growth Differentiation factor 5 (GDF5) / Transforming Growth Factor beta (TGF-beta) signalling pathway / extracellular protein.
Function / homology
Function and homology information


negative regulation of CD4-positive, alpha-beta T cell activation / ossification involved in bone remodeling / forelimb morphogenesis / chondroblast differentiation / BMP binding / hindlimb morphogenesis / negative regulation of mesenchymal cell apoptotic process / positive regulation of chondrocyte differentiation / regulation of BMP signaling pathway / mesenchymal cell apoptotic process ...negative regulation of CD4-positive, alpha-beta T cell activation / ossification involved in bone remodeling / forelimb morphogenesis / chondroblast differentiation / BMP binding / hindlimb morphogenesis / negative regulation of mesenchymal cell apoptotic process / positive regulation of chondrocyte differentiation / regulation of BMP signaling pathway / mesenchymal cell apoptotic process / negative regulation of CD4-positive, alpha-beta T cell proliferation / positive regulation of BMP signaling pathway / camera-type eye development / transforming growth factor beta binding / negative regulation of chondrocyte differentiation / embryonic limb morphogenesis / Molecules associated with elastic fibres / negative regulation of cytokine production / positive regulation of transforming growth factor beta receptor signaling pathway / forebrain development / mesoderm formation / hemopoiesis / positive regulation of SMAD protein signal transduction / regulation of multicellular organism growth / negative regulation of BMP signaling pathway / chondrocyte differentiation / negative regulation of osteoblast differentiation / response to mechanical stimulus / BMP signaling pathway / salivary gland morphogenesis / positive regulation of neuron differentiation / transforming growth factor beta receptor signaling pathway / ossification / cytokine activity / growth factor activity / negative regulation of epithelial cell proliferation / cell-cell signaling / heparin binding / negative regulation of neuron apoptotic process / extracellular space / extracellular region / identical protein binding / plasma membrane
Similarity search - Function
Twisted gastrulation (Tsg) protein / Twisted gastrulation (Tsg) protein conserved region / Twisted gastrulation (Tsg) protein N-terminal domain / TGF-beta, propeptide / TGF-beta propeptide / Transforming growth factor beta, conserved site / TGF-beta family signature. / Transforming growth factor-beta-related / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal ...Twisted gastrulation (Tsg) protein / Twisted gastrulation (Tsg) protein conserved region / Twisted gastrulation (Tsg) protein N-terminal domain / TGF-beta, propeptide / TGF-beta propeptide / Transforming growth factor beta, conserved site / TGF-beta family signature. / Transforming growth factor-beta-related / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Cystine-knot cytokine
Similarity search - Domain/homology
Growth/differentiation factor 5 / Twisted gastrulation protein homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.96 Å
AuthorsMalinauskas, T. / Rudolf, A.F. / Moore, G. / Eggington, H. / Belnoue-Davis, H. / El Omari, K. / Woolley, R.E. / Griffiths, S.C. / Duman, R. / Wagner, A. ...Malinauskas, T. / Rudolf, A.F. / Moore, G. / Eggington, H. / Belnoue-Davis, H. / El Omari, K. / Woolley, R.E. / Griffiths, S.C. / Duman, R. / Wagner, A. / Leedham, S.J. / Baldock, C. / Ashe, H. / Siebold, C.
Funding support United Kingdom, European Union, France, 4items
OrganizationGrant numberCountry
Cancer Research UKC20724/A14414 United Kingdom
Cancer Research UKC20724/A26752 United Kingdom
European Research Council (ERC)647278European Union
Human Frontier Science Program (HFSP)LT000021/2014-L France
CitationJournal: Nat Commun / Year: 2024
Title: Molecular mechanism of BMP signal control by Twisted gastrulation.
Authors: Malinauskas, T. / Moore, G. / Rudolf, A.F. / Eggington, H. / Belnoue-Davis, H.L. / El Omari, K. / Griffiths, S.C. / Woolley, R.E. / Duman, R. / Wagner, A. / Leedham, S.J. / Baldock, C. / Ashe, H.L. / Siebold, C.
History
DepositionDec 6, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 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: Growth/differentiation factor 5
B: Growth/differentiation factor 5
C: Twisted gastrulation protein homolog 1
D: Twisted gastrulation protein homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6198
Polymers42,4594
Non-polymers1604
Water2,702150
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance, TWSG1 binds to GDF5 in SPR-based experiments.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6420 Å2
ΔGint-86 kcal/mol
Surface area14760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.047, 88.588, 97.622
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Growth/differentiation factor 5 / GDF-5 / Bone morphogenetic protein 14 / BMP-14 / Cartilage-derived morphogenetic protein 1 / CDMP-1 ...GDF-5 / Bone morphogenetic protein 14 / BMP-14 / Cartilage-derived morphogenetic protein 1 / CDMP-1 / Lipopolysaccharide-associated protein 4 / LAP-4 / LPS-associated protein 4 / Radotermin


Mass: 13729.833 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GDF5, BMP14, CDMP1 / Plasmid: pET22b / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta pLysS / References: UniProt: P43026
#2: Protein Twisted gastrulation protein homolog 1


Mass: 7499.739 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TWSG1, TSG, PSEC0250 / Plasmid: pHR-CMV-TetO2-3C-mVenus-His12 / Cell line (production host): HEK293T / Organ (production host): Kidney / Production host: Homo sapiens (human) / References: UniProt: Q9GZX9
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 150 / Source method: isolated from a natural source / Formula: H2O
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: 2.9 Å3/Da / Density % sol: 57.66 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: 12.1% w/v PEG 1000, 12.1% w/v PEG 3350, 12.1% v/v MPD, 97 mM CaCl2, 0.097 M Bicine/Trizma pH 8.5
PH range: 7.5-8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 23, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.957→49.254 Å / Num. obs: 30654 / % possible obs: 84.2 % / Redundancy: 13.1 % / Biso Wilson estimate: 50.32 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.019 / Rrim(I) all: 0.067 / Net I/σ(I): 17.9
Reflection shellResolution: 1.957→2.099 Å / Redundancy: 13.7 % / Rmerge(I) obs: 1.936 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1534 / CC1/2: 0.534 / Rpim(I) all: 0.542 / Rrim(I) all: 2.011 / % possible all: 22.5

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.96→49.25 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.6748
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2119 1431 4.67 %
Rwork0.1832 29220 -
obs0.1847 30651 84.16 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 69.55 Å2
Refinement stepCycle: LAST / Resolution: 1.96→49.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2373 0 4 150 2527
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01572443
X-RAY DIFFRACTIONf_angle_d1.55013309
X-RAY DIFFRACTIONf_chiral_restr0.0704370
X-RAY DIFFRACTIONf_plane_restr0.0131429
X-RAY DIFFRACTIONf_dihedral_angle_d12.8819915
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.96-2.030.39280.2451219X-RAY DIFFRACTION6.34
2.03-2.110.2876550.25651497X-RAY DIFFRACTION43.29
2.11-2.20.28531340.24493080X-RAY DIFFRACTION90.2
2.2-2.320.28421650.22913429X-RAY DIFFRACTION99.67
2.32-2.470.25431710.18973450X-RAY DIFFRACTION100
2.47-2.660.19361810.1843417X-RAY DIFFRACTION100
2.66-2.920.27071670.2163474X-RAY DIFFRACTION99.97
2.92-3.350.22471710.18163490X-RAY DIFFRACTION99.97
3.35-4.210.20641880.1623504X-RAY DIFFRACTION99.97
4.22-49.250.18731910.17953660X-RAY DIFFRACTION99.84
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)
13.914727377770.3932089259444.642865773410.7746989559870.7867225146797.06113545497-0.260084554469-0.1417676416270.110592393458-0.1684611509580.01689996706170.0667010569439-0.145189811189-0.2049345713530.2921420845680.432507879735-0.05593973980480.04249643850620.317194314841-0.01965697856810.412840545172-14.470553548617.4400782509-13.6119025995
22.80809466087-1.417456323283.779803040743.47012284789-3.74593169437.104259684140.003543192862230.4010152484190.0770689845737-0.175482222457-0.191232227068-0.1546037719210.2284585731130.3585373617250.2088285174560.4381803636980.01155911730010.1351764161690.341226510558-0.01806571125580.392283450869-0.80931323855810.8219483056-6.10231132311
32.35527825462-1.8346247276-2.376456347624.152920196222.439724037436.57138615164-0.08856261436911.39852416254-0.948651169514-1.394594485970.158590981112-1.0674750853-0.2682368645041.13830237375-0.009921010745051.0263142011-0.09481119303480.130076589871.18300399899-0.2523055854260.904867940726-6.0754934795412.7919375559-35.0309955928
48.831097612671.10320866115-1.619364356042.394890928710.8857956488274.923126961240.0400102335414-1.03272121745-0.222435924131.09593280460.0945075693241.251356512920.306987355846-1.30439133929-0.1006316450680.7264125265150.02201845696880.2010986906450.8402841293520.179487887760.796988936121-10.59400276513.299665819114.6395018222
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain 'A' and resid 397 through 501)AA397 - 5011 - 105
22(chain 'B' and resid 398 through 501)BB398 - 5011 - 104
33(chain 'C' and resid 25 through 77)CC25 - 771 - 50
44(chain 'D' and resid 25 through 78)DD25 - 781 - 50

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