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- PDB-8y22: FGFR1 kinase domain with a covalent inhibitor 9g -

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Basic information

Entry
Database: PDB / ID: 8y22
TitleFGFR1 kinase domain with a covalent inhibitor 9g
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE / Fibroblast growth factor receptor 1
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 / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification ...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 / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / cementum mineralization / response to sodium phosphate / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / receptor-receptor interaction / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / auditory receptor cell development / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of parathyroid hormone secretion / chordate embryonic development / mesenchymal cell proliferation / paraxial mesoderm development / fibroblast growth factor receptor activity / FGFR1b ligand binding and activation / branching involved in salivary gland morphogenesis / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / positive regulation of phospholipase activity / lung-associated mesenchyme development / cell projection assembly / cellular response to fibroblast growth factor stimulus / outer ear morphogenesis / middle ear morphogenesis / skeletal system morphogenesis / embryonic limb morphogenesis / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / cardiac muscle cell proliferation / positive regulation of endothelial cell chemotaxis / ureteric bud development / midbrain development / inner ear morphogenesis / fibroblast growth factor binding / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / PI-3K cascade:FGFR1 / regulation of cell differentiation / phosphatidylinositol-mediated signaling / PI3K Cascade / positive regulation of blood vessel endothelial cell migration / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / calcium ion homeostasis / chondrocyte differentiation / : / SHC-mediated cascade:FGFR1 / cell maturation / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR1 signaling / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / stem cell proliferation / Signal transduction by L1 / skeletal system development / stem cell differentiation / positive regulation of cell differentiation / sensory perception of sound / Negative regulation of FGFR1 signaling / positive regulation of MAP kinase activity / neuron migration / receptor protein-tyrosine kinase / positive regulation of neuron projection development / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / neuron projection development / MAPK cascade / cell migration / PIP3 activates AKT signaling / heparin binding / gene expression / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / cytoplasmic vesicle / RAF/MAP kinase cascade / protein tyrosine kinase activity / angiogenesis / in utero embryonic development / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / protein phosphorylation / positive regulation of cell population proliferation / negative regulation of transcription by RNA polymerase II / protein homodimerization activity
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 / Tyrosine 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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
Similarity search - Domain/homology
: / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.792 Å
AuthorsChen, X.J. / Chen, Y.H.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82202920 China
National Natural Science Foundation of China (NSFC)82172654 China
CitationJournal: Eur.J.Med.Chem. / Year: 2024
Title: Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors.
Authors: Deng, W. / Chen, X. / Liang, H. / Song, X. / Xiang, S. / Guo, J. / Tu, Z. / Zhou, Y. / Chen, Y. / Lu, X.
History
DepositionJan 25, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)71,83811
Polymers70,2212
Non-polymers1,6189
Water68538
1
B: Fibroblast growth factor receptor 1
hetero molecules


  • defined by author
  • Evidence: gel filtration
  • 36 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)35,9676
Polymers35,1101
Non-polymers8575
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Fibroblast growth factor receptor 1
hetero molecules


  • defined by author
  • 35.9 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)35,8715
Polymers35,1101
Non-polymers7614
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)210.105, 56.922, 65.066
Angle α, β, γ (deg.)90.00, 107.47, 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 / 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: 35110.352 Da / Num. of mol.: 2 / Mutation: C127S
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 #1/H766 (bacteria)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1LW9 / ~{N}-[4-[[4-azanyl-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]phenyl]propanamide


Mass: 472.562 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H24N6O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.64 Å3/Da / Density % sol: 53.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 18% PEG 8000, 0.2 M Li2SO4, and 0.1 M MES, pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: Cu FINE FOCUS / Wavelength: 1.587 Å
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: May 17, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.587 Å / Relative weight: 1
ReflectionResolution: 2.792→46.381 Å / Num. obs: 17936 / % possible obs: 96.88 % / Redundancy: 6.7 % / Biso Wilson estimate: 47.31 Å2 / CC1/2: 0.986 / Rrim(I) all: 0.2254 / Net I/σ(I): 8
Reflection shellResolution: 2.792→2.892 Å / Mean I/σ(I) obs: 2.9 / Num. unique obs: 1467 / CC1/2: 0.791 / % possible all: 80.08

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data scaling
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7WCL

7wcl


Resolution: 2.792→46.381 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 27.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2597 966 5.39 %
Rwork0.1937 --
obs0.1973 17923 96.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.792→46.381 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4568 0 103 38 4709
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0054766
X-RAY DIFFRACTIONf_angle_d0.7666450
X-RAY DIFFRACTIONf_dihedral_angle_d13.5981804
X-RAY DIFFRACTIONf_chiral_restr0.024696
X-RAY DIFFRACTIONf_plane_restr0.002817
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.792-2.93910.39571340.28512036X-RAY DIFFRACTION83
2.9391-3.12320.33361510.26292394X-RAY DIFFRACTION97
3.1232-3.36430.30941510.24142435X-RAY DIFFRACTION99
3.3643-3.70270.28781180.19632494X-RAY DIFFRACTION99
3.7027-4.23820.24671230.17412510X-RAY DIFFRACTION100
4.2382-5.33850.21861450.16392503X-RAY DIFFRACTION100
5.3385-46.3810.20321440.16822585X-RAY DIFFRACTION100

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