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- PDB-8xlo: FGFR1 kinase domain with a dual-warhead covalent inhibitor CXF-007 -

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Basic information

Entry
Database: PDB / ID: 8xlo
TitleFGFR1 kinase domain with a dual-warhead covalent inhibitor CXF-007
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/INHIBITOR / Fibroblast growth factor receptor 1 / 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 / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway ...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 / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / vitamin D3 metabolic process / cementum mineralization / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / 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 / receptor-receptor interaction / chordate embryonic development / positive regulation of parathyroid hormone secretion / auditory receptor cell development / mesenchymal cell proliferation / paraxial mesoderm development / FGFR1b ligand binding and activation / regulation of postsynaptic density assembly / Signaling by activated point mutants of FGFR1 / fibroblast growth factor receptor activity / 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 / middle ear morphogenesis / skeletal system morphogenesis / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / midbrain development / fibroblast growth factor binding / positive regulation of MAP kinase activity / regulation of cell differentiation / PI3K Cascade / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / chondrocyte differentiation / cardiac muscle cell proliferation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / positive regulation of cardiac muscle cell proliferation / cell maturation / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / peptidyl-tyrosine phosphorylation / stem cell proliferation / Signal transduction by L1 / skeletal system development / stem cell differentiation / positive regulation of cell differentiation / Negative regulation of FGFR1 signaling / sensory perception of sound / positive regulation of neuron projection development / receptor protein-tyrosine kinase / neuron migration / neuron projection development / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / MAPK cascade / heparin binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / cytoplasmic vesicle / protein tyrosine kinase activity / angiogenesis / gene expression / in utero embryonic development / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / postsynapse / positive regulation of MAPK cascade / 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 / 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 / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.36 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 selective covalent inhibitors of FGFR4.
Authors: Chen, X. / Li, H. / Lin, Q. / Dai, S. / Qu, L. / Guo, M. / Zhang, L. / Liao, J. / Wei, H. / Xu, G. / Jiang, L. / Chen, Y.
History
DepositionDec 26, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)72,34510
Polymers70,5292
Non-polymers1,8168
Water66737
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1725
Polymers35,2651
Non-polymers9084
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1725
Polymers35,2651
Non-polymers9084
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)209.210, 57.480, 66.410
Angle α, β, γ (deg.)90.00, 107.86, 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: 35264.520 Da / Num. of mol.: 2 / Mutation: C584S
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-A1LVQ / CXF007 / ~{N}-[4-[2-[3-(3,5-dimethoxyphenyl)-2-oxidanylidene-7-[[2-(prop-2-enoylamino)phenyl]amino]-4~{H}-pyrimido[4,5-d]pyrimidin-1-yl]ethyl]phenyl]propanamide


Mass: 619.670 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H33N7O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.7 Å3/Da / Density % sol: 54.45 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: 18% (w/v) PEG 8000, 0.2 M Li2SO4, and 0.1 M MES, pH 6.5

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 31, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.36→46.683 Å / Num. obs: 31130 / % possible obs: 99.61 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.07077 / Rrim(I) all: 0.077 / Net I/σ(I): 14.79
Reflection shellResolution: 2.36→2.444 Å / Redundancy: 7.1 % / Rmerge(I) obs: 1.112 / Mean I/σ(I) obs: 2.12 / Num. unique obs: 3091 / CC1/2: 0.801 / Rrim(I) all: 1.201 / % possible all: 99.87

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
DIALSdata reduction
EVAL15data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7WCL

7wcl


Resolution: 2.36→46.683 Å / SU ML: 0.34 / Cross valid method: NONE / σ(F): 1.35 / Phase error: 32.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2545 1422 4.57 %
Rwork0.2079 --
obs0.2101 31101 99.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.36→46.683 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4498 0 122 37 4657
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034727
X-RAY DIFFRACTIONf_angle_d0.6476420
X-RAY DIFFRACTIONf_dihedral_angle_d13.2691793
X-RAY DIFFRACTIONf_chiral_restr0.024698
X-RAY DIFFRACTIONf_plane_restr0.003827
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3601-2.44440.38121250.32232964X-RAY DIFFRACTION100
2.4444-2.54230.40041500.30112934X-RAY DIFFRACTION100
2.5423-2.6580.33181570.27142973X-RAY DIFFRACTION100
2.658-2.79810.32811490.26512900X-RAY DIFFRACTION100
2.7981-2.97340.31230.24522963X-RAY DIFFRACTION100
2.9734-3.20290.29651220.23783008X-RAY DIFFRACTION100
3.2029-3.52510.26441440.22862963X-RAY DIFFRACTION100
3.5251-4.0350.26151560.19832955X-RAY DIFFRACTION100
4.035-5.08260.22631460.17082974X-RAY DIFFRACTION100
5.0826-46.680.20071500.18213045X-RAY DIFFRACTION99

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