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

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Basic information

Entry
Database: PDB / ID: 8bwn
TitleCrystal structure of human Twisted gastrulation protein homolog 1 (TWSG1) in complex with human Growth Differentiation Factor 5 (GDF5) and calcium, long-wavelength X-ray dataset (4010 eV)
Components
  • Growth/differentiation factor 5
  • Twisted gastrulation protein homolog 1
KeywordsSIGNALING PROTEIN / Twisted gastrulation protein homolog 1 (TWSG1) / Transforming Growth Factor beta (TGF-beta) signalling pathway / Growth Differentiation Factor 5 (GDF5) / long-wavelength X-rays.
Function / homology
Function and homology information


negative regulation of CD4-positive, alpha-beta T cell activation / ossification involved in bone remodeling / forelimb morphogenesis / BMP binding / chondroblast differentiation / 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 / BMP binding / chondroblast differentiation / 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 / negative regulation of cytokine production / Molecules associated with elastic fibres / positive regulation of transforming growth factor beta receptor signaling pathway / hemopoiesis / mesoderm formation / negative regulation of BMP signaling pathway / positive regulation of SMAD protein signal transduction / regulation of multicellular organism growth / negative regulation of osteoblast differentiation / chondrocyte differentiation / BMP signaling pathway / salivary gland morphogenesis / response to mechanical stimulus / forebrain development / 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: 2.57 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 7, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 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

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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)42,5797
Polymers42,4594
Non-polymers1203
Water81145
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: surface plasmon resonance, TWSG1 binds to GDF5 in SPR-based experiments.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.574, 89.178, 97.681
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
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 398 through 431 or resid 433...
d_2ens_1(chain "B" and (resid 398 through 431 or resid 433...
d_1ens_2(chain "C" and (resid 25 through 48 or resid 53 through 77))
d_2ens_2(chain "D" and resid 25 through 77)

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1ALAGLYA2 - 35
d_12ens_1CYSHISA37 - 44
d_13ens_1GLUTHRA46 - 73
d_14ens_1LEUARGA75 - 105
d_21ens_1ALAGLYB1 - 34
d_22ens_1CYSHISB36 - 43
d_23ens_1GLUTHRB45 - 72
d_24ens_1LEUARGB74 - 104
d_11ens_2GLYPROC1 - 24
d_12ens_2CYSCYSC26 - 50
d_21ens_2GLYCYSD1 - 49

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(-0.653986782657, -0.756250423929, 0.0196617501275), (-0.756343494792, 0.653086817542, -0.0377110943656), (0.0156782012828, -0.0395335940798, -0.999095235172)23.3166050968, 11.2779471239, 20.4329990633
2given(-0.654248992763, -0.753939734294, 0.0594401591594), (-0.756188443514, 0.653364545942, -0.0359695426999), (-0.0117172251341, -0.0684809985186, -0.997583610269)22.2695832766, 10.8847170114, 21.4016923623

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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 / Details (production host): 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 / 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.: 3 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 2.95 Å3/Da / Density % sol: 58.35 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 12.5% w/v PEG 1000, 12.5% w/v PEG 3350, 12.5% v/v MPD, 100 mM CaCl2, 0.1 M MOPS/HEPES-Na pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I23 / Wavelength: 3.09187 Å
DetectorType: DECTRIS PILATUS 12M / Detector: PIXEL / Date: Feb 17, 2022
RadiationMonochromator: Silicon crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 3.09187 Å / Relative weight: 1
ReflectionResolution: 2.567→65.86 Å / Num. obs: 12005 / % possible obs: 72 % / Redundancy: 10.2 % / Biso Wilson estimate: 83.72 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.092 / Rpim(I) all: 0.029 / Rrim(I) all: 0.097 / Net I/σ(I): 13.5
Reflection shellResolution: 2.567→2.845 Å / Redundancy: 10.1 % / Rmerge(I) obs: 1.59 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 600 / CC1/2: 0.599 / Rpim(I) all: 0.52 / Rrim(I) all: 1.674 / % possible all: 13.9

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Processing

Software
NameVersionClassification
autoPROC1.0.5 (20211020)data reduction
PHENIX1.20.1_4487refinement
XDSJan 10, 2022 (BUILT 20220110)data reduction
Aimless0.7.7data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.57→65.86 Å / SU ML: 0.3705 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 38.6184
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2829 552 4.6 %
Rwork0.2515 11451 -
obs0.2529 12003 72.01 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 94.27 Å2
Refinement stepCycle: LAST / Resolution: 2.57→65.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2373 0 3 45 2421
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00172449
X-RAY DIFFRACTIONf_angle_d0.41123319
X-RAY DIFFRACTIONf_chiral_restr0.0386372
X-RAY DIFFRACTIONf_plane_restr0.0028430
X-RAY DIFFRACTIONf_dihedral_angle_d9.1907919
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AX-RAY DIFFRACTIONTorsion NCS0.668963409255
ens_2d_2CX-RAY DIFFRACTIONTorsion NCS0.445145989997
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.57-2.820.3985220.4237490X-RAY DIFFRACTION12.55
2.83-3.230.33031380.32922914X-RAY DIFFRACTION74.17
3.23-4.070.27611830.26693939X-RAY DIFFRACTION99.33
4.07-65.860.27682090.23154108X-RAY DIFFRACTION99.93
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)
13.99721250368-0.522951026845.743012877582.09384663491-1.190111447179.06051899155-0.490325901026-0.02446056884690.2833527406150.1778910416860.0895367140435-0.220481637086-0.5904699576920.1566272459720.3504145041740.4429395112380.03489864138740.1035877625540.4075997643740.04695790033470.49975126411914.620495811817.504349167113.5774545939
23.302383160090.3531926547033.415830572373.515463987833.022889713177.54756114103-0.129415685705-0.3115174666280.07927409378360.00111454350954-0.1790372735550.3282657299410.0705007417735-0.5093141272730.3184811406850.502568506357-0.07637213976760.1448066158780.3851335091560.008418252704060.5583194732690.85184425250110.95910664936.16259351165
34.438487338021.370457190711.445236350671.06025144362-1.242476033527.19437842555-0.0807946568691-2.08449412106-0.8768916218271.08194423169-0.1138752618670.484177067812-0.283534542452-1.35299631223-0.0854008195871.069184040880.1234009721820.1926706060271.204875829020.3861456341450.9533929299146.0544747149112.813203888635.156914746
43.051280117471.69004890623-1.095896019353.74930414584-1.75869389475.863631839230.06682808320921.51245028697-0.27239731881-1.52000461610.445075425304-0.563444438724-0.04756170058730.728739916509-0.3860144417910.860197020665-0.02043551587620.2427550361080.808421089737-0.1195652353850.82659754909610.802576334613.5006904338-14.7562001835
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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