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- PDB-8fxs: Crystal structure of human pro-TGF-beta2 in complex with Nb9 -

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Basic information

Entry
Database: PDB / ID: 8fxs
TitleCrystal structure of human pro-TGF-beta2 in complex with Nb9
Components
  • Nanobody clone 9
  • 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: 3.15 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: Transforming growth factor beta-2 proprotein
D: Nanobody clone 9
E: Nanobody clone 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,4386
Polymers117,9954
Non-polymers4422
Water724
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12150 Å2
ΔGint-79 kcal/mol
Surface area42740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.683, 89.554, 89.740
Angle α, β, γ (deg.)90.00, 95.00, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 2 / Mutation: C24S, N140R, R298_R303delinsG
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFB2 / Variant: Isoform 1 / Cell line (production host): Expi293 GnTI-/- / Production host: Homo sapiens (human) / References: UniProt: P61812
#2: Antibody Nanobody clone 9


Mass: 13802.190 Da / Num. of mol.: 2
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.: 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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 2.37 Å3/Da / Density % sol: 48.17 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: Crystals of the Nb9/proTGF-beta2 complex (1 microliter) were formed in hanging drops with 1 microliter of 100 mM HEPES pH 7.6, 10% PEG 4000.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.92009 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Sep 2, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92009 Å / Relative weight: 1
ReflectionResolution: 3.15→48.27 Å / Num. obs: 18849 / % possible obs: 98.27 % / Redundancy: 3.4 % / CC1/2: 0.967 / Net I/σ(I): 8.48
Reflection shellResolution: 3.15→3.263 Å / Redundancy: 3.6 % / Num. unique obs: 1881 / CC1/2: 0.423 / % possible all: 99.37

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDS20190417data reduction
XDS20190417data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.15→48.27 Å / SU ML: 0.54 / Cross valid method: FREE R-VALUE / σ(F): 1.2 / Phase error: 31.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3009 1908 10.12 %
Rwork0.2493 --
obs0.2546 18849 98.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.15→48.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6706 0 0 4 6710
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002
X-RAY DIFFRACTIONf_angle_d0.543
X-RAY DIFFRACTIONf_dihedral_angle_d3.935916
X-RAY DIFFRACTIONf_chiral_restr0.043990
X-RAY DIFFRACTIONf_plane_restr0.0051178
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.15-3.230.4031340.3611210X-RAY DIFFRACTION100
3.23-3.320.36851430.32291218X-RAY DIFFRACTION99
3.32-3.410.34481370.29721181X-RAY DIFFRACTION99
3.41-3.520.35081190.28241259X-RAY DIFFRACTION99
3.52-3.650.31411310.27431189X-RAY DIFFRACTION99
3.65-3.80.33271390.28341212X-RAY DIFFRACTION99
3.8-3.970.35531460.3121186X-RAY DIFFRACTION98
3.97-4.180.30821330.23511215X-RAY DIFFRACTION99
4.18-4.440.3021370.20521206X-RAY DIFFRACTION98
4.44-4.780.24511360.20621206X-RAY DIFFRACTION98
4.78-5.260.24321310.21191214X-RAY DIFFRACTION98
5.26-6.020.29591500.25191210X-RAY DIFFRACTION98
6.02-7.580.35651330.27121208X-RAY DIFFRACTION97
7.59-48.270.24911390.22421227X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: -17.4657 Å / Origin y: -3.4026 Å / Origin z: 6.9835 Å
111213212223313233
T0.5429 Å2-0.0004 Å20.0129 Å2-0.5895 Å2-0.0083 Å2--0.6622 Å2
L0.5156 °2-0.2331 °20.1056 °2-0.469 °2-0.0942 °2--0.6775 °2
S0.0058 Å °-0.0107 Å °-0.0228 Å °0.0318 Å °-0.0409 Å °-0.0016 Å °0.0188 Å °-0.0132 Å °0.0313 Å °
Refinement TLS groupSelection details: all

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