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- PDB-6mzq: TAS-120 in reversible binding mode with FGFR1 -

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Basic information

Entry
Database: PDB / ID: 6mzq
TitleTAS-120 in reversible binding mode with FGFR1
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / FGFR1 / TAS-120 / inhibitor / complex / 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 / 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 / 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 / auditory receptor cell development / 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 / 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 / skeletal system morphogenesis / middle ear morphogenesis / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / Formation of paraxial mesoderm / positive regulation of stem cell proliferation / midbrain development / fibroblast growth factor binding / regulation of cell differentiation / PI3K Cascade / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / cardiac muscle cell proliferation / chondrocyte differentiation / fibroblast growth factor receptor activity / positive regulation of MAP kinase activity / calcium ion homeostasis / cell maturation / SHC-mediated cascade:FGFR1 / positive regulation of cardiac muscle cell proliferation / cellular response to fibroblast growth factor stimulus / FRS-mediated FGFR1 signaling / Signaling by FGFR1 in disease / positive regulation of neuron differentiation / NCAM signaling for neurite out-growth / SH2 domain binding / Negative regulation of FGFR1 signaling / Signal transduction by L1 / stem cell proliferation / skeletal system development / positive regulation of cell differentiation / stem cell differentiation / sensory perception of sound / peptidyl-tyrosine phosphorylation / receptor protein-tyrosine kinase / 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 / protein autophosphorylation / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / cytoplasmic vesicle / protein tyrosine kinase activity / angiogenesis / in utero embryonic development / gene expression / receptor complex / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / postsynapse / positive regulation of MAPK cascade / protein phosphorylation / 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-TZ0 / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsKalyukina, M. / Squire, C.J.
CitationJournal: ChemMedChem / Year: 2019
Title: TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure.
Authors: Kalyukina, M. / Yosaatmadja, Y. / Middleditch, M.J. / Patterson, A.V. / Smaill, J.B. / Squire, C.J.
History
DepositionNov 5, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 16, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 30, 2019Group: Data collection / Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.name
Revision 1.2Mar 6, 2019Group: Data collection / Database references
Category: citation / database_PDB_rev ...citation / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 11, 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

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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)71,5444
Polymers70,7072
Non-polymers8372
Water3,045169
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7722
Polymers35,3541
Non-polymers4181
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)35,7722
Polymers35,3541
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)208.800, 49.157, 64.684
Angle α, β, γ (deg.)90.00, 106.10, 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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR / Plasmid: pET DUet / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-TZ0 / 1-[(3S)-3-{4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}pyrrolidin-1-yl]prop-2-en-1-one


Mass: 418.448 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H22N6O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 169 / 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: 2.26 Å3/Da / Density % sol: 45.46 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: MPEG 5000, sodium cacodylate, ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2→100 Å / Num. obs: 41723 / % possible obs: 97.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7 % / CC1/2: 0.999 / Net I/σ(I): 12.7
Reflection shellResolution: 2→2.06 Å / Redundancy: 6.9 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2849 / CC1/2: 0.926 / % possible all: 90.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0230refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5UR1

5ur1


Resolution: 2→47.33 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.955 / SU B: 4.8 / SU ML: 0.129 / Cross valid method: THROUGHOUT / ESU R: 0.174 / ESU R Free: 0.155 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22984 1964 4.7 %RANDOM
Rwork0.19434 ---
obs0.19606 39758 97.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 42.725 Å2
Baniso -1Baniso -2Baniso -3
1-0.21 Å20 Å2-0.12 Å2
2---0.13 Å2-0 Å2
3----0 Å2
Refinement stepCycle: 1 / Resolution: 2→47.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4046 0 62 169 4277
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0144221
X-RAY DIFFRACTIONr_bond_other_d0.0020.0173776
X-RAY DIFFRACTIONr_angle_refined_deg1.4141.6735747
X-RAY DIFFRACTIONr_angle_other_deg0.9821.6518779
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5795535
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.99822.312186
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.36715668
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9311524
X-RAY DIFFRACTIONr_chiral_restr0.0680.2552
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024730
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02740
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_it3.5314.362155
X-RAY DIFFRACTIONr_mcbond_other3.5244.3592154
X-RAY DIFFRACTIONr_mcangle_it4.9296.5152682
X-RAY DIFFRACTIONr_mcangle_other4.9296.5162683
X-RAY DIFFRACTIONr_scbond_it4.3944.6922066
X-RAY DIFFRACTIONr_scbond_other4.3934.6952067
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.4656.893065
X-RAY DIFFRACTIONr_long_range_B_refined7.82449.7354689
X-RAY DIFFRACTIONr_long_range_B_other7.82849.6624672
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.057 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.304 134 -
Rwork0.299 2732 -
obs--90.41 %

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