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- PDB-4rwk: Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584... -

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Basic information

Entry
Database: PDB / ID: 4rwk
TitleCrystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M) in complex with N-{3-[2-(3,5-DIMETHOXYPHENYL)ETHYL]-1H-PYRAZOL-5-YL}-4-[(3R,5S)-3,5-DIMETHYLPIPERAZIN-1-YL]BENZAMIDE (AZD4547)
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / receptor tyrosine kinase / gatekeeper mutation / proto-oncogene / 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-66T / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.982 Å
AuthorsSohl, C.D. / Anderson, K.S.
CitationJournal: Acs Chem.Biol. / Year: 2015
Title: Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles' Heel of Targeted Therapy.
Authors: Sohl, C.D. / Ryan, M.R. / Luo, B. / Frey, K.M. / Anderson, K.S.
History
DepositionDec 4, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2015Provider: repository / Type: Initial release
Revision 1.1May 27, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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: Fibroblast growth factor receptor 1
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,4695
Polymers72,5172
Non-polymers9513
Water1267
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7473
Polymers36,2591
Non-polymers4882
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)36,7222
Polymers36,2591
Non-polymers4641
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)211.424, 49.397, 66.502
Angle α, β, γ (deg.)90.000, 107.260, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
22

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111chain A and segidA0
212chain B and segidB0

NCS ensembles :
ID
1
2

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Components

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


Mass: 36258.664 Da / Num. of mol.: 2 / Fragment: Residues 458-765 / Mutation: C488A, C584S, V561M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BFGFR, CEK, FGFBR, FGFR1, FLG, FLT2, HBGFR / Plasmid: pET-28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-66T / N-{3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-5-yl}-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide


Mass: 463.572 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H33N5O3
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / 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: 2.29 Å3/Da / Density % sol: 46.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.6
Details: 0.1 M MES pH 6.6, 34% PEG 8000, 0.2 M ammonium sulfate, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 27, 2014 / Details: monochrometer
RadiationMonochromator: Cryogenically cooled double crystal monochrometer with horizontal focusing sagittal bend second mono crystal with 4:1 magnification ratio and vertically focusing mirror.
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.98→50 Å / Num. obs: 13606 / % possible obs: 99.2 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 44.34 Å2 / Rsym value: 0.108 / Net I/σ(I): 17.095
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.98-3.033.40.337192.2
3.03-3.093.80.334199.1
3.09-3.153.80.29199.1
3.15-3.213.80.245198.8
3.21-3.283.80.23199.6
3.28-3.363.80.201199.2
3.36-3.443.80.178199.4
3.44-3.533.80.167199.6
3.53-3.643.80.138199.4
3.64-3.753.80.129199.6
3.75-3.893.70.122199.4
3.89-4.043.80.1199.4
4.04-4.233.70.096199.6
4.23-4.453.70.093199.7
4.45-4.733.70.086199.6
4.73-5.093.70.086199.7
5.09-5.613.70.084199.7
5.61-6.423.70.076199.9
6.42-8.083.60.0591100
8.08-503.50.0411100

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.15data extraction
CBASSdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4RWI

4rwi


Resolution: 2.982→47.982 Å / SU ML: 0.41 / σ(F): 1.36 / Phase error: 31.29 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2986 1363 10.02 %
Rwork0.2376 --
obs0.2439 13597 99.29 %
all-13597 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.804 Å2
Refinement stepCycle: LAST / Resolution: 2.982→47.982 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4477 0 69 7 4553
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034650
X-RAY DIFFRACTIONf_angle_d0.6736319
X-RAY DIFFRACTIONf_dihedral_angle_d12.2321694
X-RAY DIFFRACTIONf_chiral_restr0.027706
X-RAY DIFFRACTIONf_plane_restr0.004813
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDType
11A2422X-RAY DIFFRACTIONTORSIONAL
12B2422X-RAY DIFFRACTIONTORSIONAL
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9824-3.0890.4331320.32131210X-RAY DIFFRACTION98
3.089-3.21270.35371330.30731188X-RAY DIFFRACTION99
3.2127-3.35890.40121330.29711195X-RAY DIFFRACTION99
3.3589-3.53590.30971380.25311232X-RAY DIFFRACTION99
3.5359-3.75730.31591320.2451211X-RAY DIFFRACTION99
3.7573-4.04730.27381360.23721218X-RAY DIFFRACTION99
4.0473-4.45430.26081370.21111224X-RAY DIFFRACTION100
4.4543-5.09830.28151390.20081222X-RAY DIFFRACTION100
5.0983-6.42090.27881390.23061245X-RAY DIFFRACTION100
6.4209-47.9880.25071440.20071289X-RAY DIFFRACTION100

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