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- PDB-2x7o: Crystal structure of TGFbRI complexed with an indolinone inhibitor -

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Basic information

Entry
Database: PDB / ID: 2x7o
TitleCrystal structure of TGFbRI complexed with an indolinone inhibitor
ComponentsTGF-BETA RECEPTOR TYPE I
KeywordsTRANSFERASE / KINASE / GLYCOPROTEIN
Function / homology
Function and homology information


extracellular structure organization / epicardium morphogenesis / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / myofibroblast differentiation / positive regulation of tight junction disassembly / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / TGFBR2 Kinase Domain Mutants in Cancer / transforming growth factor beta receptor activity ...extracellular structure organization / epicardium morphogenesis / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / myofibroblast differentiation / positive regulation of tight junction disassembly / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / TGFBR2 Kinase Domain Mutants in Cancer / transforming growth factor beta receptor activity / positive regulation of mesenchymal stem cell proliferation / ventricular compact myocardium morphogenesis / mesenchymal cell differentiation / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / TGFBR3 regulates TGF-beta signaling / positive regulation of vasculature development / activin receptor activity, type I / regulation of epithelial to mesenchymal transition / cardiac epithelial to mesenchymal transition / activin receptor complex / transforming growth factor beta receptor activity, type I / neuron fate commitment / positive regulation of extracellular matrix assembly / TGFBR1 LBD Mutants in Cancer / type II transforming growth factor beta receptor binding / angiogenesis involved in coronary vascular morphogenesis / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / pharyngeal system development / activin binding / germ cell migration / coronary artery morphogenesis / activin receptor signaling pathway / embryonic cranial skeleton morphogenesis / ventricular trabecula myocardium morphogenesis / filopodium assembly / response to cholesterol / transforming growth factor beta binding / I-SMAD binding / negative regulation of chondrocyte differentiation / skeletal system morphogenesis / collagen fibril organization / endothelial cell activation / endothelial cell proliferation / lens development in camera-type eye / positive regulation of filopodium assembly / anterior/posterior pattern specification / artery morphogenesis / ventricular septum morphogenesis / roof of mouth development / negative regulation of endothelial cell proliferation / SMAD binding / TGF-beta receptor signaling activates SMADs / positive regulation of SMAD protein signal transduction / blastocyst development / regulation of protein ubiquitination / epithelial to mesenchymal transition / endothelial cell migration / bicellular tight junction / positive regulation of epithelial to mesenchymal transition / cellular response to transforming growth factor beta stimulus / positive regulation of stress fiber assembly / positive regulation of endothelial cell proliferation / post-embryonic development / transforming growth factor beta receptor signaling pathway / Downregulation of TGF-beta receptor signaling / thymus development / kidney development / negative regulation of cell migration / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / skeletal system development / cell motility / negative regulation of extrinsic apoptotic signaling pathway / positive regulation of apoptotic signaling pathway / wound healing / cellular response to growth factor stimulus / male gonad development / UCH proteinases / heart development / nervous system development / peptidyl-serine phosphorylation / positive regulation of cell growth / regulation of gene expression / in utero embryonic development / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / regulation of cell cycle / protein kinase activity / intracellular signal transduction / Ub-specific processing proteases / endosome / positive regulation of cell migration / membrane raft / protein serine/threonine kinase activity / ubiquitin protein ligase binding / positive regulation of cell population proliferation / regulation of DNA-templated transcription / positive regulation of gene expression / apoptotic process
Similarity search - Function
GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / Activin types I and II receptor domain / Activin types I and II receptor domain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / Activin types I and II receptor domain / Activin types I and II receptor domain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-ZOP / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.7 Å
AuthorsRoth, G.J. / Heckel, A. / Brandl, T. / Grauert, M. / Hoerer, S. / Kley, J.T. / Schnapp, G. / Baum, P. / Mennerich, D. / Schnapp, A. / Park, J.E.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Design, Synthesis and Evaluation of Indolinones as Inhibitors of the Transforming Growth Factor Beta Receptor I (Tgfbri)
Authors: Roth, G.J. / Heckel, A. / Brandl, T. / Grauert, M. / Hoerer, S. / Kley, J.T. / Schnapp, G. / Baum, P. / Mennerich, D. / Schnapp, A. / Park, J.E.
History
DepositionMar 3, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 20, 2010Provider: repository / Type: Initial release
Revision 1.1May 19, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Apr 3, 2019Group: Data collection / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc / pdbx_database_status
Item: _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_strain / _pdbx_database_status.recvd_author_approval
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: TGF-BETA RECEPTOR TYPE I
B: TGF-BETA RECEPTOR TYPE I
C: TGF-BETA RECEPTOR TYPE I
D: TGF-BETA RECEPTOR TYPE I
E: TGF-BETA RECEPTOR TYPE I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)197,07610
Polymers194,6035
Non-polymers2,4735
Water00
1
A: TGF-BETA RECEPTOR TYPE I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4152
Polymers38,9211
Non-polymers4951
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TGF-BETA RECEPTOR TYPE I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4152
Polymers38,9211
Non-polymers4951
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: TGF-BETA RECEPTOR TYPE I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4152
Polymers38,9211
Non-polymers4951
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: TGF-BETA RECEPTOR TYPE I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4152
Polymers38,9211
Non-polymers4951
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: TGF-BETA RECEPTOR TYPE I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4152
Polymers38,9211
Non-polymers4951
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)179.929, 246.561, 131.617
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(0.9318, 0.2761, 0.2355), (-0.3256, 0.3494, 0.8786), (0.1603, -0.8954, 0.4155)-32.94, -17.51, 100.7
2given(0.8001, 0.173, 0.5743), (-0.2323, -0.7934, 0.5627), (0.553, -0.5836, -0.5946)-47.79, 78.71, 145.2
3given(0.7434, -0.2002, 0.6382), (0.2099, -0.8361, -0.5069), (0.6351, 0.5108, -0.5795)-27.59, 146.4, 66.39
4given(0.9243, -0.2478, 0.2904), (0.3565, 0.2881, -0.8888), (0.1366, 0.925, 0.3546)-3.19, 100.1, -6.906

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Components

#1: Protein
TGF-BETA RECEPTOR TYPE I / TGFR-1 / TRANSFORMING GROWTH FACTOR-BETA RECEPTOR TYPE I / TGF-BETA RECEPTOR TYPE I / TBETAR-I / ...TGFR-1 / TRANSFORMING GROWTH FACTOR-BETA RECEPTOR TYPE I / TGF-BETA RECEPTOR TYPE I / TBETAR-I / TGF-BETA TYPE I RECEPTOR / SERINE/THREONINE-PROTEIN KINASE RECEPTOR / R4SKR4 / ACTIVIN RECEPTOR-LIKE KINASE 5 / ALK-5


Mass: 38920.641 Da / Num. of mol.: 5 / Fragment: CYTOPLASMIC DOMAIN, RESIDUES 162-503
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PDEST10 / Cell line (production host): High Five / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P36897, receptor protein serine/threonine kinase
#2: Chemical
ChemComp-ZOP / (3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE


Mass: 494.627 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C31H34N4O2

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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: 3.8 Å3/Da / Density % sol: 67 % / Description: ONLY ONE CRYSTAL COULD BE OBTAINED
Crystal growpH: 7.2 / Details: 1.5 M AMMONIUM SULFATE, 0.1 M GLYCINE PH 7.25

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.0339
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 16, 2004 / Details: MIRRORS
RadiationMonochromator: SILICIUM / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0339 Å / Relative weight: 1
ReflectionResolution: 3.7→22.7 Å / Num. obs: 24744 / % possible obs: 79.2 % / Observed criterion σ(I): 2 / Redundancy: 3.7 % / Biso Wilson estimate: 57.41 Å2 / Rmerge(I) obs: 0.02 / Net I/σ(I): 4.7
Reflection shellResolution: 3.7→3.9 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.07 / Mean I/σ(I) obs: 1.9 / % possible all: 81

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Processing

Software
NameVersionClassification
BUSTER2.9.3refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1IAS

1ias


Resolution: 3.7→22.72 Å / Cor.coef. Fo:Fc: 0.6966 / Cor.coef. Fo:Fc free: 0.6596 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.777 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2732 1260 5.09 %RANDOM
Rwork0.267 ---
obs0.2673 24744 78.63 %-
Displacement parametersBiso mean: 53.01 Å2
Baniso -1Baniso -2Baniso -3
1-24.852 Å20 Å20 Å2
2---44.3146 Å20 Å2
3---19.4626 Å2
Refine analyzeLuzzati coordinate error obs: 0.961 Å
Refinement stepCycle: LAST / Resolution: 3.7→22.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13145 0 185 0 13330
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00713615HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.8918395HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4810SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes310HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1975HARMONIC5
X-RAY DIFFRACTIONt_it13615HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion1.42
X-RAY DIFFRACTIONt_other_torsion21.17
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1745SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact14581SEMIHARMONIC4
LS refinement shellResolution: 3.7→3.86 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2744 160 5.21 %
Rwork0.2563 2913 -
all0.2572 3073 -
obs--78.63 %
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)
10.0016-0.06410.02220.02810.00730-0.00020.001-0.00050.00070.00010.00210.00050.00010.0001-0.00120.0047-0.01-0.00050.0051-0.005386.403149.076367.353
20.0034-0.0106-0.0060.00970.07270-0.0002-0.0001-0.00030.0005-0.0003-0.0010.0014-0.00010.00050.00430.0042-0.0014-0.0002-0.00170.000580.992944.65852.3458
30.0083-0.0493-0.06030-0.09780-0.00010.0008-0.00140.00050.0005-0.00170.001-0.0001-0.0004-0.0060.00140.0027-0.002-0.0001-0.000784.169886.082672.7714
40.0015-0.0192-0.00620.06010.0460.0089-0.0001-0.0001-0.0007-0.0016-0.00050.00030.0010.00060.00060.00180.00590.00270.00090.00120.001178.137996.521761.3052
500.0313-0.08680.0573-0.049800.00010.0006-0.00140.0010.0021-0.0005-0.0008-0.0006-0.0022-0.0047-0.00340.0071-0.00040.0038-0.001571.054792.1013106.663
60.01010.0264-0.02550.0549-0.05540.02640.0001-0.00040.00040.00180.0007-0.0028-0.00040.0011-0.00080.0054-0.00010.00750.00230.00070.008459.4006103.366109.87
70.0524-0.00940.15840.020.00620.12610.00020.00040.0022-0.0038-0.0005-0.0027-0.0049-0.00050.00030.0013-0.0057-0.0110.002-0.00050.002164.8859.0695121.64
80.0034-0.0126-0.00030.00240.01230-0.0001-0.00060.00030.00060.0006-0.0008-0.00010.001-0.0005-0.0005-0.00050.00280.0006-0.00260.002250.449556.128129.113
90-0.02520.08310.0124-0.02240-0.00060.00030.00090.0010.0003-0.00080.0006-0.00150.0003-0.0035-0.0025-0.00750.0008-0.0009-0.003474.801131.805197.6472
100.0056-0.0044-0.021300.00530.0201-0.0001-0.0002-0.00020.0014-0.0003-0.00310.000100.00040.0015-0.0004-0.0020.00040.00080.00166.288417.840794.3752
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(A171 - A283)
2X-RAY DIFFRACTION2(A284 - A500)
3X-RAY DIFFRACTION3(B171 - B283)
4X-RAY DIFFRACTION4(B284 - B500)
5X-RAY DIFFRACTION5(C171 - C283)
6X-RAY DIFFRACTION6(C284 - C500)
7X-RAY DIFFRACTION7(D171 - D283)
8X-RAY DIFFRACTION8(D284 - D500)
9X-RAY DIFFRACTION9(E171 - E283)
10X-RAY DIFFRACTION10(E284 - E500)

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