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- PDB-8fxv: Crystal structure of human proTGF-beta2 in complex with Nb18 -

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Basic information

Entry
Database: PDB / ID: 8fxv
TitleCrystal structure of human proTGF-beta2 in complex with Nb18
Components
  • Nanobody clone 18
  • Transforming growth factor beta-2 proprotein
KeywordsCYTOKINE / TGF-b TGF-beta nanobody latent procomplex prodomain
Function / homology
Function and homology information


regulation of timing of catagen / regulation of apoptotic process involved in outflow tract morphogenesis / substantia propria of cornea development / negative regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / ascending aorta morphogenesis / uterine wall breakdown / cardioblast differentiation / positive regulation of timing of catagen / positive regulation of cardioblast differentiation / positive regulation of heart contraction ...regulation of timing of catagen / regulation of apoptotic process involved in outflow tract morphogenesis / substantia propria of cornea development / negative regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / ascending aorta morphogenesis / uterine wall breakdown / cardioblast differentiation / positive regulation of timing of catagen / positive regulation of cardioblast differentiation / positive regulation of heart contraction / cardiac right ventricle morphogenesis / pharyngeal arch artery morphogenesis / type III transforming growth factor beta receptor binding / regulation of transforming growth factor beta2 production / atrial septum morphogenesis / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / negative regulation of macrophage cytokine production / signaling / secondary palate development / glial cell migration / somatic stem cell division / heart valve morphogenesis / endocardial cushion fusion / atrial septum primum morphogenesis / membranous septum morphogenesis / positive regulation of integrin biosynthetic process / cardiac epithelial to mesenchymal transition / eye development / cranial skeletal system development / positive regulation of stress-activated MAPK cascade / embryonic digestive tract development / neural retina development / transforming growth factor beta receptor binding / type II transforming growth factor beta receptor binding / pulmonary valve morphogenesis / outflow tract septum morphogenesis / ventricular trabecula myocardium morphogenesis / cell-cell junction organization / negative regulation of Ras protein signal transduction / collagen fibril organization / positive regulation of cell adhesion mediated by integrin / embryonic limb morphogenesis / embryo development ending in birth or egg hatching / odontogenesis / dopamine biosynthetic process / Molecules associated with elastic fibres / atrioventricular valve morphogenesis / cardiac muscle cell proliferation / endocardial cushion morphogenesis / hair follicle morphogenesis / generation of neurons / ventricular septum morphogenesis / positive regulation of Notch signaling pathway / activation of protein kinase activity / positive regulation of epithelial cell migration / TGF-beta receptor signaling activates SMADs / uterus development / positive regulation of SMAD protein signal transduction / inner ear development / hemopoiesis / positive regulation of cell division / hair follicle development / ECM proteoglycans / neuron development / epithelial to mesenchymal transition / positive regulation of cell cycle / positive regulation of epithelial to mesenchymal transition / salivary gland morphogenesis / heart morphogenesis / extrinsic apoptotic signaling pathway / epithelial cell differentiation / negative regulation of angiogenesis / neutrophil chemotaxis / transforming growth factor beta receptor signaling pathway / platelet alpha granule lumen / kidney development / skeletal system development / neural tube closure / cytokine activity / response to progesterone / positive regulation of protein secretion / growth factor activity / wound healing / cell morphogenesis / negative regulation of cell growth / positive regulation of miRNA transcription / response to wounding / negative regulation of epithelial cell proliferation / male gonad development / positive regulation of immune response / positive regulation of neuron apoptotic process / cell migration / Platelet degranulation / heart development / amyloid-beta binding / regulation of cell population proliferation / positive regulation of cell growth / collagen-containing extracellular matrix / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / response to hypoxia
Similarity search - Function
Transforming growth factor beta-2 proprotein / Transforming growth factor-beta / 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 ...Transforming growth factor beta-2 proprotein / Transforming growth factor-beta / 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
Transforming growth factor beta-2 proprotein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsLe, V.Q. / Springer, T.A.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)2R01HL159714 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)1K01DK124443 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)5T32DK007527 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2023
Title: A specialized integrin-binding motif enables proTGF-beta 2 activation by integrin alpha V beta 6 but not alpha V beta 8.
Authors: Le, V.Q. / Zhao, B. / Ramesh, S. / Toohey, C. / DeCosta, A. / Mintseris, J. / Liu, X. / Gygi, S. / Springer, T.A.
History
DepositionJan 25, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 21, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transforming growth factor beta-2 proprotein
B: Nanobody clone 18
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,9363
Polymers58,7152
Non-polymers2211
Water1,13563
1
A: Transforming growth factor beta-2 proprotein
B: Nanobody clone 18
hetero molecules

A: Transforming growth factor beta-2 proprotein
B: Nanobody clone 18
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,8736
Polymers117,4304
Non-polymers4422
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_656-x+1,y,-z+11
Buried area12100 Å2
ΔGint-69 kcal/mol
Surface area40730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.750, 78.160, 88.890
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21221

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Components

#1: Protein Transforming growth factor beta-2 proprotein / Cetermin / Glioblastoma-derived T-cell suppressor factor / G-TSF


Mass: 45195.441 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFB2 / Cell line (production host): HEK293S GnTI-/- / Production host: Homo sapiens (human) / References: UniProt: P61812
#2: Antibody Nanobody clone 18


Mass: 13519.787 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli BL21(DE3) (bacteria)
#3: 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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 63 / Source method: isolated from a natural source / Formula: H2O
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: 2.09 Å3/Da / Density % sol: 41.03 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: Crystals of the Nb18/proTGF-beta2 complex (1 microliter) were formed in hanging drops with 1 microliter of 100 mM HEPES pH 7.4, 26.7% Jeffamine ED2001.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.03321 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 17, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03321 Å / Relative weight: 1
ReflectionResolution: 2.2→44.44 Å / Num. obs: 25659 / % possible obs: 99.78 % / Redundancy: 6.5 % / CC1/2: 0.998 / Net I/σ(I): 10.11
Reflection shellResolution: 2.2→2.279 Å / Num. unique obs: 2538 / CC1/2: 0.212

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDS20190417data reduction
XDS20190417data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→45.17 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 0.16 / Phase error: 30.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2491 2345 4.88 %
Rwork0.2268 --
obs0.2279 48073 99.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→45.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3483 0 0 63 3546
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053561
X-RAY DIFFRACTIONf_angle_d0.7534812
X-RAY DIFFRACTIONf_dihedral_angle_d13.971330
X-RAY DIFFRACTIONf_chiral_restr0.05518
X-RAY DIFFRACTIONf_plane_restr0.006617
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.240.37211440.35712718X-RAY DIFFRACTION100
2.24-2.290.3651410.34752681X-RAY DIFFRACTION100
2.29-2.350.40511390.34352694X-RAY DIFFRACTION100
2.35-2.410.34311330.32862667X-RAY DIFFRACTION99
2.41-2.470.37551260.32082707X-RAY DIFFRACTION100
2.47-2.540.36311350.30862683X-RAY DIFFRACTION99
2.54-2.630.31461570.30232711X-RAY DIFFRACTION100
2.63-2.720.33961240.32713X-RAY DIFFRACTION99
2.72-2.830.32221380.29232682X-RAY DIFFRACTION100
2.83-2.960.30641290.28052705X-RAY DIFFRACTION100
2.96-3.110.27131380.24122690X-RAY DIFFRACTION99
3.11-3.310.24211340.22062683X-RAY DIFFRACTION99
3.31-3.560.26041490.21842713X-RAY DIFFRACTION100
3.56-3.920.21571580.19382673X-RAY DIFFRACTION99
3.92-4.490.18731410.17012667X-RAY DIFFRACTION99
4.49-5.650.16211180.1692673X-RAY DIFFRACTION98
5.65-45.170.2631410.21332668X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: 31.2588 Å / Origin y: 44.2504 Å / Origin z: 30.9094 Å
111213212223313233
T0.2222 Å20.017 Å2-0.0064 Å2-0.3427 Å2-0.0306 Å2--0.3585 Å2
L0.3158 °20.3897 °20.0565 °2-1.8158 °2-0.9873 °2--1.4807 °2
S-0.0834 Å °0.0511 Å °0.0592 Å °-0.213 Å °0.1245 Å °0.2355 Å °-0.0715 Å °-0.0637 Å °-0.0538 Å °
Refinement TLS groupSelection details: all

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