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- PDB-7v29: Crystal structure of FGFR4 with a dual-warhead covalent inhhibitor -

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Basic information

Entry
Database: PDB / ID: 7v29
TitleCrystal structure of FGFR4 with a dual-warhead covalent inhhibitor
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE / Inhibitor / Dual-warhead / Fibroblast growth factor receptor 4 / Covalent
Function / homology
Function and homology information


FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / fibroblast growth factor receptor activity / Phospholipase C-mediated cascade; FGFR4 / positive regulation of DNA biosynthetic process / positive regulation of catalytic activity ...FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / fibroblast growth factor receptor activity / Phospholipase C-mediated cascade; FGFR4 / positive regulation of DNA biosynthetic process / positive regulation of catalytic activity / fibroblast growth factor binding / PI-3K cascade:FGFR4 / positive regulation of proteolysis / regulation of lipid metabolic process / PI3K Cascade / fibroblast growth factor receptor signaling pathway / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / transport vesicle / FRS-mediated FGFR4 signaling / cholesterol homeostasis / Negative regulation of FGFR4 signaling / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / glucose homeostasis / heparin binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein autophosphorylation / positive regulation of ERK1 and ERK2 cascade / receptor complex / endosome / positive regulation of cell population proliferation / positive regulation of gene expression / Golgi apparatus / endoplasmic reticulum / 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. / Immunoglobulin subtype ...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 / 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
Chem-5JR / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.983 Å
AuthorsChen, X.J. / Jiang, L.Y. / Dai, S.Y. / Qu, L.Z. / Chen, Y.H.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81974074 China
National Natural Science Foundation of China (NSFC)81570537 China
CitationJournal: Commun Chem / Year: 2022
Title: Structure-based design of a dual-warhead covalent inhibitor of FGFR4.
Authors: Chen, X. / Li, H. / Lin, Q. / Dai, S. / Yue, S. / Qu, L. / Li, M. / Guo, M. / Wei, H. / Li, J. / Jiang, L. / Xu, G. / Chen, Y.
History
DepositionAug 7, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
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
B: Fibroblast growth factor receptor 4
A: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,1329
Polymers69,3902
Non-polymers1,7427
Water7,584421
1
B: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6145
Polymers34,6951
Non-polymers9194
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint4 kcal/mol
Surface area14580 Å2
MethodPISA
2
A: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5184
Polymers34,6951
Non-polymers8233
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1530 Å2
ΔGint-16 kcal/mol
Surface area14600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.421, 61.314, 76.531
Angle α, β, γ (deg.)90.000, 112.050, 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: 34695.059 Da / Num. of mol.: 2 / Mutation: R664E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4, JTK2, TKF
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P22455, receptor protein-tyrosine kinase
#2: Chemical ChemComp-5JR / N-[2-[[3-(3,5-dimethoxyphenyl)-2-oxidanylidene-1-[3-(4-propanoylpiperazin-1-yl)propyl]-4H-pyrimido[4,5-d]pyrimidin-7-yl]amino]phenyl]propanamide


Mass: 630.737 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H42N8O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 421 / 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: 2.18 Å3/Da / Density % sol: 43.46 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 0.1 M Bis-Tris (pH 4.5), 0.2 M Li2SO4, 20% PEG 3350

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Data collection

DiffractionMean temperature: 85 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97915 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: 0.97915 Å / Relative weight: 1
ReflectionResolution: 1.983→64.345 Å / Num. obs: 41464 / % possible obs: 99.81 % / Redundancy: 6.7 % / Biso Wilson estimate: 21.75 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.116 / Rrim(I) all: 0.1262 / Net I/σ(I): 10.96
Reflection shellResolution: 1.983→2.053 Å / Rmerge(I) obs: 0.3257 / Mean I/σ(I) obs: 2.37 / Num. unique obs: 4064 / CC1/2: 0.944

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QRC

4qrc


Resolution: 1.983→64.345 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.241 2000 4.84 %
Rwork0.1914 39351 -
obs0.1938 41351 99.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 98.61 Å2 / Biso mean: 27.8686 Å2 / Biso min: 8.7 Å2
Refinement stepCycle: final / Resolution: 1.983→64.345 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4569 0 117 421 5107
Biso mean--36.03 34.54 -
Num. residues----583
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0064807
X-RAY DIFFRACTIONf_angle_d0.9616526
X-RAY DIFFRACTIONf_chiral_restr0.044693
X-RAY DIFFRACTIONf_plane_restr0.005848
X-RAY DIFFRACTIONf_dihedral_angle_d14.0131851
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.983-2.03220.30561470.234270398
2.0322-2.08710.29491290.21862828100
2.0871-2.14860.26681400.20762771100
2.1486-2.21790.29321430.21242837100
2.2179-2.29720.25521580.2112788100
2.2972-2.38920.2461300.19732815100
2.3892-2.49790.24681490.18562813100
2.4979-2.62960.20251400.1882821100
2.6296-2.79430.25511450.19052792100
2.7943-3.01010.23961410.18572830100
3.0101-3.3130.2531500.18662820100
3.313-3.79240.23711410.17532837100
3.7924-4.77770.1971420.16532822100
4.7777-64.3450.23251450.2097287498

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