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- PDB-6c18: FGFR1 kinase complex with inhibitor SN37115 -

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Basic information

Entry
Database: PDB / ID: 6c18
TitleFGFR1 kinase complex with inhibitor SN37115
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / 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 / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process ...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 / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / cementum mineralization / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / receptor-receptor interaction / response to sodium phosphate / auditory receptor cell development / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / chordate embryonic development / positive regulation of parathyroid hormone secretion / mesenchymal cell proliferation / paraxial mesoderm development / regulation of postsynaptic density assembly / FGFR1b ligand binding and activation / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / branching involved in salivary gland morphogenesis / Phospholipase C-mediated cascade: FGFR1 / positive regulation of phospholipase activity / lung-associated mesenchyme development / cell projection assembly / outer ear morphogenesis / embryonic limb morphogenesis / positive regulation of vascular endothelial cell proliferation / positive regulation of endothelial cell chemotaxis / skeletal system morphogenesis / positive regulation of mesenchymal cell proliferation / middle ear morphogenesis / ureteric bud development / cardiac muscle cell proliferation / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / midbrain development / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / fibroblast growth factor binding / regulation of cell differentiation / PI3K Cascade / cellular response to fibroblast growth factor stimulus / positive regulation of blood vessel endothelial cell migration / fibroblast growth factor receptor signaling pathway / epithelial to mesenchymal transition / chondrocyte differentiation / SHC-mediated cascade:FGFR1 / calcium ion homeostasis / cell maturation / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR1 signaling / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / positive regulation of MAP kinase activity / positive regulation of neuron differentiation / SH2 domain binding / Signal transduction by L1 / stem cell proliferation / skeletal system development / positive regulation of cell differentiation / stem cell differentiation / sensory perception of sound / Negative regulation of FGFR1 signaling / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / positive regulation of neuron projection development / neuron migration / neuron projection development / Constitutive Signaling by Aberrant PI3K in Cancer / MAPK cascade / cell migration / PIP3 activates AKT signaling / heparin binding
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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase); domain 1 / 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-YY5 / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsYosaatmadja, Y. / Smaill, J.B. / Squire, C.J.
Funding support New Zealand, 1items
OrganizationGrant numberCountry
Health REsearch Council of New ZEaland New Zealand
CitationJournal: To Be Published
Title: Understanding the structural requirements for covalent inhibition of FGFR1-3
Authors: Yosaatmadja, Y. / Squire, C.J. / Patterson, A.V. / Smaill, J.B.
History
DepositionJan 4, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 16, 2019Provider: 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)71,9885
Polymers70,7072
Non-polymers1,2813
Water30617
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0423
Polymers35,3541
Non-polymers6892
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)35,9462
Polymers35,3541
Non-polymers5931
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)208.962, 49.837, 65.085
Angle α, β, γ (deg.)90.00, 106.19, 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 / Fragment: UNP residues 457-763 / Mutation: C486A, C582S
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-YY5 / 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{(3S)-1-[(2E)-4-(dimethylamino)but-2-enoyl]pyrrolidin-3-yl}-7-[(propan-2-yl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one


Mass: 592.517 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H35Cl2N7O4
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 2.3 Å3/Da / Density % sol: 46.56 %
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: 110 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jan 24, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→19.78 Å / Num. obs: 28937 / % possible obs: 99.8 % / Redundancy: 7.4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.142 / Rpim(I) all: 0.06 / Net I/σ(I): 11.8
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 7.3 % / Mean I/σ(I) obs: 1.5 / Num. unique all: 2836 / Num. unique obs: 2836 / CC1/2: 0.599 / Rpim(I) all: 0.612 / % 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: 2.3→19.78 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.912 / SU B: 20.985 / SU ML: 0.232 / Cross valid method: THROUGHOUT / ESU R: 0.332 / ESU R Free: 0.245 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26668 1377 4.8 %RANDOM
Rwork0.22269 ---
obs0.22481 27539 99.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 44.145 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å2-0 Å20.8 Å2
2---1.31 Å2-0 Å2
3---0.57 Å2
Refinement stepCycle: 1 / Resolution: 2.3→19.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4096 0 83 17 4196
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194332
X-RAY DIFFRACTIONr_bond_other_d0.0020.024109
X-RAY DIFFRACTIONr_angle_refined_deg1.5091.9955890
X-RAY DIFFRACTIONr_angle_other_deg0.8583.0049446
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4785537
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.93124.343175
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.51215719
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.911525
X-RAY DIFFRACTIONr_chiral_restr0.1040.2664
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214829
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02914
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_it1.5542.6642157
X-RAY DIFFRACTIONr_mcbond_other1.5512.6632156
X-RAY DIFFRACTIONr_mcangle_it2.5983.9862688
X-RAY DIFFRACTIONr_mcangle_other2.5993.9872689
X-RAY DIFFRACTIONr_scbond_it1.7712.8632175
X-RAY DIFFRACTIONr_scbond_other1.7662.8572172
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.9234.2113196
X-RAY DIFFRACTIONr_long_range_B_refined4.50321.5114857
X-RAY DIFFRACTIONr_long_range_B_other4.50221.5154856
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.36 96 -
Rwork0.31 2035 -
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)
12.0906-0.21650.82041.0508-0.69053.86880.09190.0032-0.11670.0487-0.02460.10370.21790.0211-0.06740.0417-0.0267-0.01080.12780.01410.0236-18.577616.81773.7057
22.0772-0.48891.47711.5045-0.83053.17390.0025-0.13820.05170.1490.01960.0777-0.0543-0.065-0.0220.07520.0084-0.03080.1821-0.01320.0354-44.825340.639222.275
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A465 - 765
2X-RAY DIFFRACTION2B466 - 762

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