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- PDB-5ur1: FGFR1 kinase domain complex with SN37333 in reversible binding mode -

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Basic information

Entry
Database: PDB / ID: 5ur1
TitleFGFR1 kinase domain complex with SN37333 in reversible binding mode
ComponentsFibroblast growth factor receptor 1
Keywordstransferase/transferase inhibitor / transferase / transferase-transferase inhibitor complex
Function / homology
Function and homology information


Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway ...Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / vitamin D3 metabolic process / cementum mineralization / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / response to sodium phosphate / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of phospholipase activity / receptor-receptor interaction / chordate embryonic development / positive regulation of parathyroid hormone secretion / auditory receptor cell development / mesenchymal cell proliferation / paraxial mesoderm development / FGFR1b ligand binding and activation / regulation of postsynaptic density assembly / Signaling by activated point mutants of FGFR1 / fibroblast growth factor receptor activity / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / branching involved in salivary gland morphogenesis / Phospholipase C-mediated cascade: FGFR1 / lung-associated mesenchyme development / cell projection assembly / outer ear morphogenesis / embryonic limb morphogenesis / positive regulation of endothelial cell chemotaxis / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / ureteric bud development / middle ear morphogenesis / skeletal system morphogenesis / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / midbrain development / fibroblast growth factor binding / positive regulation of MAP kinase activity / regulation of cell differentiation / PI3K Cascade / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / chondrocyte differentiation / cardiac muscle cell proliferation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / positive regulation of cardiac muscle cell proliferation / cell maturation / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / peptidyl-tyrosine phosphorylation / stem cell proliferation / Signal transduction by L1 / skeletal system development / stem cell differentiation / positive regulation of cell differentiation / Negative regulation of FGFR1 signaling / sensory perception of sound / positive regulation of neuron projection development / receptor protein-tyrosine kinase / neuron migration / neuron projection development / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / MAPK cascade / heparin binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / cytoplasmic vesicle / protein tyrosine kinase activity / angiogenesis / gene expression / in utero embryonic development / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / postsynapse / positive regulation of MAPK cascade / positive regulation of cell population proliferation / glutamatergic synapse
Similarity search - Function
Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor receptor family / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain ...Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor receptor family / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / 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-YY9 / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsYosaatmadja, Y. / Paik, W.-K. / Smaill, J.B. / Squire, C.J.
CitationJournal: Eur J Med Chem / Year: 2017
Title: 2-Oxo-3, 4-dihydropyrimido[4, 5-d]pyrimidinyl derivatives as new irreversible pan fibroblast growth factor receptor (FGFR) inhibitors.
Authors: Li, X. / Guise, C.P. / Taghipouran, R. / Yosaatmadja, Y. / Ashoorzadeh, A. / Paik, W.K. / Squire, C.J. / Jiang, S. / Luo, J. / Xu, Y. / Tu, Z.C. / Lu, X. / Ren, X. / Patterson, A.V. / Smaill, J.B. / Ding, K.
History
DepositionFeb 9, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 31, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 1
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,9884
Polymers70,7072
Non-polymers1,2812
Water93752
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9942
Polymers35,3541
Non-polymers6411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9942
Polymers35,3541
Non-polymers6411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)213.050, 51.783, 66.070
Angle α, β, γ (deg.)90.00, 106.87, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Fibroblast growth factor receptor 1 / FGFR-1 / Basic fibroblast growth factor receptor 1 / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 ...FGFR-1 / Basic fibroblast growth factor receptor 1 / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / N-sam / Proto-oncogene c-Fgr


Mass: 35353.613 Da / Num. of mol.: 2 / Mutation: C488A, C584S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR / Production host: Escherichia coli (E. coli)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-YY9 / 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{1-[4-(dimethylamino)but-2-enoyl]piperidin-4-yl}-7-(phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one


Mass: 640.560 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H35Cl2N7O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 52 / Source method: isolated from a natural source / Formula: H2O

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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: 2.47 Å3/Da / Density % sol: 50.13 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 20% MPEG 5000, 0.1 M sodium cacodylate pH 7.5, 0.2 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Aug 24, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.2→19.54 Å / Num. obs: 35322 / % possible obs: 99.8 % / Redundancy: 14.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.154 / Rpim(I) all: 0.041 / Net I/σ(I): 18.4
Reflection shellResolution: 2.2→2.27 Å / Redundancy: 15 % / Mean I/σ(I) obs: 2.4 / Num. unique all: 3440 / Num. unique obs: 3248 / CC1/2: 0.736 / Rpim(I) all: 0.349 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WUN

4wun


Resolution: 2.2→19.54 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.905 / SU B: 17.593 / SU ML: 0.192 / Cross valid method: THROUGHOUT / ESU R: 0.261 / ESU R Free: 0.222 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27658 1758 5 %RANDOM
Rwork0.22715 ---
obs0.2296 33557 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.735 Å2
Baniso -1Baniso -2Baniso -3
1--0.29 Å20 Å20.38 Å2
2--0.42 Å2-0 Å2
3----0.3 Å2
Refinement stepCycle: 1 / Resolution: 2.2→19.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4161 0 79 52 4292
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0194341
X-RAY DIFFRACTIONr_bond_other_d0.0010.024109
X-RAY DIFFRACTIONr_angle_refined_deg1.3831.9995893
X-RAY DIFFRACTIONr_angle_other_deg0.7823.0049449
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7725537
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.23824.302172
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.03415725
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8391525
X-RAY DIFFRACTIONr_chiral_restr0.0930.2659
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214841
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02912
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2292.6022169
X-RAY DIFFRACTIONr_mcbond_other1.2292.6012168
X-RAY DIFFRACTIONr_mcangle_it2.0473.892699
X-RAY DIFFRACTIONr_mcangle_other2.0473.892700
X-RAY DIFFRACTIONr_scbond_it1.2572.6262172
X-RAY DIFFRACTIONr_scbond_other1.2572.6262173
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.0423.8973194
X-RAY DIFFRACTIONr_long_range_B_refined3.41920.0974845
X-RAY DIFFRACTIONr_long_range_B_other3.40820.0984837
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.37 129 -
Rwork0.341 2448 -
obs--100 %
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)
12.2636-0.09750.79940.8855-0.68913.33930.0484-0.0699-0.10020.0434-0.02590.06110.16310.017-0.02250.04170.01070.01180.1642-0.00920.0126-18.3399-8.79183.877
21.8751-0.46461.45491.0153-0.87543.40120.0014-0.2910.00550.13810.01460.0506-0.013-0.0448-0.0160.11490.01390.0210.0751-0.00630.0579-46.643915.216422.4498
313.1-12.0555-10.188113.19689.40327.9246-0.35950.6434-1.34890.4286-0.68071.21060.2904-0.50411.04020.22790.0434-0.03230.2946-0.03540.1712-32.5603-0.479922.2666
40.6473-0.1845-0.35080.27960.00320.28570.01050.00530.03010.0259-0.02370.0109-0.05980.10670.01320.1061-0.0415-0.03730.21220.03220.0203-32.50715.38267.5995
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A464 - 765
2X-RAY DIFFRACTION2B464 - 763
3X-RAY DIFFRACTION3A801
4X-RAY DIFFRACTION3B801
5X-RAY DIFFRACTION4A901 - 928
6X-RAY DIFFRACTION4B901 - 924

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