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- PDB-7wcl: Crystal structure of FGFR1 kinase domain with Pemigatinib -

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Basic information

Entry
Database: PDB / ID: 7wcl
TitleCrystal structure of FGFR1 kinase domain with Pemigatinib
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Inhibitor / Complex / STRUCTURAL PROTEIN / TRANSFERASE-TRANSFERASE INHIBITOR complex / TRA
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-8ZF / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.495 Å
AuthorsChen, X.J. / Lin, Q.M. / Jiang, L.Y. / Qu, L.Z. / Chen, Y.H.
Funding support3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81570537
National Natural Science Foundation of China (NSFC)81974074
National Natural Science Foundation of China (NSFC)82172654
CitationJournal: Commun Chem / Year: 2022
Title: Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants.
Authors: Lin, Q. / Chen, X. / Qu, L. / Guo, M. / Wei, H. / Dai, S. / Jiang, L. / Chen, Y.
History
DepositionDec 20, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 14, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)72,08010
Polymers70,5292
Non-polymers1,5518
Water1,62190
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1366
Polymers35,2651
Non-polymers8725
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint-17 kcal/mol
Surface area15200 Å2
MethodPISA
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9444
Polymers35,2651
Non-polymers6803
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)210.831, 49.594, 66.804
Angle α, β, γ (deg.)90.000, 107.500, 90.000
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-8ZF / 11-[2,6-bis(fluoranyl)-3,5-dimethoxy-phenyl]-13-ethyl-4-(morpholin-4-ylmethyl)-5,7,11,13-tetrazatricyclo[7.4.0.0^{2,6}]trideca-1(9),2(6),3,7-tetraen-12-one / Pemigatinib


Mass: 487.499 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H27F2N5O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, anticancer, inhibitor*YM
#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.: 90 / 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: 2.37 Å3/Da / Density % sol: 48.02 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 18% (w/v) PEG 8000, 0.2 M LiSO4, 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: Aug 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.587 Å / Relative weight: 1
ReflectionResolution: 2.495→39.87 Å / Num. obs: 21761 / % possible obs: 93.45 % / Redundancy: 4.5 % / Biso Wilson estimate: 39.19 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.06982 / Rrim(I) all: 0.07907 / Net I/σ(I): 15.13
Reflection shellResolution: 2.495→2.584 Å / Redundancy: 3 % / Rmerge(I) obs: 0.2876 / Mean I/σ(I) obs: 3.05 / Num. unique obs: 1416 / CC1/2: 0.922 / % possible all: 61.78

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Processing

Software
NameVersionClassification
HKL-3000data scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RWJ

4rwj


Resolution: 2.495→39.866 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 25.31 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2301 1089 5.01 %
Rwork0.1931 20641 -
obs0.1949 21730 93.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 113.74 Å2 / Biso mean: 44.4646 Å2 / Biso min: 23.66 Å2
Refinement stepCycle: final / Resolution: 2.495→39.866 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4598 0 100 90 4788
Biso mean--48.13 39.99 -
Num. residues----593
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034811
X-RAY DIFFRACTIONf_angle_d0.6946545
X-RAY DIFFRACTIONf_chiral_restr0.024709
X-RAY DIFFRACTIONf_plane_restr0.004835
X-RAY DIFFRACTIONf_dihedral_angle_d13.1731819
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.4951-2.60870.3123970.2429175764
2.6087-2.74620.29991280.2289232485
2.7462-2.91820.26711460.2334267298
2.9182-3.14340.27761320.22472741100
3.1434-3.45960.24951380.21092751100
3.4596-3.95980.21681820.19142737100
3.9598-4.98740.20311300.16232793100
4.9874-39.8660.19341360.17382866100

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