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- PDB-7wcx: Crystal structure of FGFR4(V550M) kinase domain with 7v -

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Basic information

Entry
Database: PDB / ID: 7wcx
TitleCrystal structure of FGFR4(V550M) kinase domain with 7v
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Inhibitor / STRUCTURAL PROTEIN / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / positive regulation of catalytic activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / fibroblast growth factor receptor activity / positive regulation of DNA biosynthetic process ...FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / positive regulation of catalytic activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / fibroblast growth factor receptor activity / positive regulation of DNA biosynthetic process / PI-3K cascade:FGFR4 / fibroblast growth factor binding / regulation of lipid metabolic process / positive regulation of proteolysis / PI3K Cascade / fibroblast growth factor receptor signaling pathway / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / transport vesicle / FRS-mediated FGFR4 signaling / peptidyl-tyrosine phosphorylation / cholesterol homeostasis / Negative regulation of FGFR4 signaling / receptor protein-tyrosine kinase / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / glucose homeostasis / PIP3 activates AKT signaling / heparin binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of ERK1 and ERK2 cascade / receptor complex / endosome / positive regulation of cell population proliferation / positive regulation of gene expression / endoplasmic reticulum / Golgi apparatus / extracellular region / ATP binding / plasma membrane
Similarity search - Function
Fibroblast growth factor receptor family / 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. ...Fibroblast growth factor receptor family / 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-90F / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.175 Å
AuthorsChen, X.J. / Lin, Q.M. / Dai, S.Y. / Chen, Y.H.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81570537 China
National Natural Science Foundation of China (NSFC)81974074 China
National Natural Science Foundation of China (NSFC)82172654 China
CitationJournal: J.Med.Chem. / Year: 2022
Title: Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.
Authors: Shao, M. / Chen, X. / Yang, F. / Song, X. / Zhou, Y. / Lin, Q. / Fu, Y. / Ortega, R. / Lin, X. / Tu, Z. / Patterson, A.V. / Smaill, J.B. / Chen, Y. / Lu, X.
History
DepositionDec 20, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 6, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Sep 17, 2025Group: Advisory / Derived calculations / Structure summary
Category: pdbx_entry_details / pdbx_validate_close_contact / struct_conn
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 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5826
Polymers34,5411
Non-polymers1,0415
Water3,729207
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area720 Å2
ΔGint-48 kcal/mol
Surface area15440 Å2
Unit cell
Length a, b, c (Å)41.964, 61.342, 60.813
Angle α, β, γ (deg.)90.000, 98.060, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Fibroblast growth factor receptor 4 / FGFR-4


Mass: 34540.895 Da / Num. of mol.: 1 / Mutation: C477A, R664E,variant V550M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4, JTK2, TKF / Production host: Escherichia coli (E. coli)
References: UniProt: P22455, receptor protein-tyrosine kinase
#2: Chemical ChemComp-90F / ~{N}-[2-[[5-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-1~{H}-indazol-3-yl]amino]-3-fluoranyl-5-(4-morpholin-4-ylpiperidin-1-yl)phenyl]propanamide


Mass: 656.578 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H36Cl2FN7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 207 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.24 Å3/Da / Density % sol: 45.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 0.1 M Bis-Tris (pH 4.5), 0.2 M Li2SO4, 16-19 % PEG 3350

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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: Oct 8, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.587 Å / Relative weight: 1
ReflectionResolution: 2.175→42.971 Å / Num. obs: 14797 / % possible obs: 91.39 % / Redundancy: 6.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.0781 / Rrim(I) all: 0.08453 / Net I/σ(I): 18.67
Reflection shellResolution: 2.175→2.253 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.22 / Mean I/σ(I) obs: 5.71 / Num. unique obs: 1036 / CC1/2: 0.953 / % possible all: 64.11

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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: 7WCT

7wct


Resolution: 2.175→42.971 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 24.2 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2214 711 4.81 %
Rwork0.1701 14084 -
obs0.1726 14795 91.38 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 129.43 Å2 / Biso mean: 30.627 Å2 / Biso min: 7.95 Å2
Refinement stepCycle: final / Resolution: 2.175→42.971 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2347 0 65 207 2619
Biso mean--44.34 34.59 -
Num. residues----300
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032475
X-RAY DIFFRACTIONf_angle_d0.7413367
X-RAY DIFFRACTIONf_chiral_restr0.026356
X-RAY DIFFRACTIONf_plane_restr0.003436
X-RAY DIFFRACTIONf_dihedral_angle_d13.164951
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.1755-2.34340.26831050.1887209568
2.3434-2.57920.24931400.1963270389
2.5792-2.95240.23141470.19043061100
2.9524-3.71940.23161540.16853100100
3.7194-42.9710.19451650.1523125100

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