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

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Basic information

Entry
Database: PDB / ID: 4rwi
TitleCrystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo
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 / Formation of paraxial mesoderm / positive regulation of stem cell proliferation / fibroblast growth factor binding / regulation of cell differentiation / PI3K Cascade / cellular response to fibroblast growth factor stimulus / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / epithelial to mesenchymal transition / chondrocyte differentiation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / 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 / Transferase(Phosphotransferase); domain 1 / 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
Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.292 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 / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _struct_ref_seq_dif.details

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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


Theoretical massNumber of molelcules
Total (without water)72,5172
Polymers72,5172
Non-polymers00
Water1,47782
1
A: Fibroblast growth factor receptor 1


Theoretical massNumber of molelcules
Total (without water)36,2591
Polymers36,2591
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Fibroblast growth factor receptor 1


Theoretical massNumber of molelcules
Total (without water)36,2591
Polymers36,2591
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)211.061, 50.550, 66.529
Angle α, β, γ (deg.)90.000, 107.690, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1

Dom-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1VALVALGLNGLNchain AAA460 - 76412 - 316
2SERSERASNASNchain BBB461 - 76313 - 315

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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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / 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: 2.33 Å3/Da / Density % sol: 47.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: 0.1 M sodium cacodylate pH 6.4, 30% 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: 2.29→50 Å / Num. obs: 30355 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 28.86 Å2 / Rsym value: 0.054 / Χ2: 2.066 / Net I/σ(I): 36.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.29-2.333.40.17714271.538196
2.33-2.373.80.16815261.603199.7
2.37-2.423.70.15214961.566199.7
2.42-2.473.80.14814961.699199.7
2.47-2.523.80.13415111.624199.8
2.52-2.583.80.11714921.73199.8
2.58-2.643.80.11115131.7641100
2.64-2.723.70.11715062.6111100
2.72-2.793.70.08615401.8611100
2.79-2.893.80.07915071.8541100
2.89-2.993.80.0715131.9461100
2.99-3.113.70.06215261.9381100
3.11-3.253.70.05714952.0461100
3.25-3.423.70.04915192.0051100
3.42-3.633.70.0515412.9951100
3.63-3.923.70.04715382.7511100
3.92-4.313.70.04315102.6551100
4.31-4.933.70.04515473.066199.9
4.93-6.213.60.03715532.0061100
6.21-503.60.0315991.973199.3

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACT3.15data extraction
CBASSdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 3KY2

3ky2


Resolution: 2.292→47.499 Å / SU ML: 0.26 / Cross valid method: Rfree Flag / σ(F): 1.34 / Phase error: 25.19 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2362 1526 5.03 %Random
Rwork0.1854 ---
obs0.188 30345 99.78 %-
all-30345 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 94.51 Å2 / Biso mean: 34.5232 Å2 / Biso min: 13.09 Å2
Refinement stepCycle: LAST / Resolution: 2.292→47.499 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4528 0 0 82 4610
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094625
X-RAY DIFFRACTIONf_angle_d1.1336275
X-RAY DIFFRACTIONf_chiral_restr0.047702
X-RAY DIFFRACTIONf_plane_restr0.006811
X-RAY DIFFRACTIONf_dihedral_angle_d13.8331714
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2418X-RAY DIFFRACTION5.897TORSIONAL
12B2418X-RAY DIFFRACTION5.897TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.292-2.36550.30181320.22222556268899
2.3655-2.45010.26941320.206525962728100
2.4501-2.54820.26311440.211625992743100
2.5482-2.66410.26751350.209826302765100
2.6641-2.80460.29931390.207925952734100
2.8046-2.98030.27921420.224826022744100
2.9803-3.21030.26341380.21826092747100
3.2103-3.53330.26571360.203526232759100
3.5333-4.04430.21891400.165826392779100
4.0443-5.09450.19581400.148126492789100
5.0945-47.50870.17541480.153227212869100

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