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- PDB-7yc3: Crystal structure of FGFR4 kinase domain with 10t -

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Basic information

Entry
Database: PDB / ID: 7yc3
TitleCrystal structure of FGFR4 kinase domain with 10t
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE/INHIBITOR / Kinase / Inhibitor / STRUCTURAL PROTEIN / TRANSFERASE-TRANSFERASE INHIBITOR complex / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / fibroblast growth factor receptor activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / positive regulation of catalytic activity / positive regulation of DNA biosynthetic process ...FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / fibroblast growth factor receptor activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / positive regulation of catalytic activity / positive regulation of DNA biosynthetic process / 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 / FRS-mediated FGFR4 signaling / transport vesicle / 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. ...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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / 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
Chem-IIW / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.987 Å
AuthorsChen, X.J. / Lin, Q.M. / 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 5-Formyl-pyrrolo[3,2- b ]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors.
Authors: Yang, F. / Chen, X. / Song, X. / Ortega, R. / Lin, X. / Deng, W. / Guo, J. / Tu, Z. / Patterson, A.V. / Smaill, J.B. / Chen, Y. / Lu, X.
History
DepositionJun 30, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 16, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 23, 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

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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)35,8168
Polymers34,6951
Non-polymers1,1217
Water4,216234
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1110 Å2
ΔGint-35 kcal/mol
Surface area15460 Å2
Unit cell
Length a, b, c (Å)42.333, 61.038, 60.516
Angle α, β, γ (deg.)90.000, 98.010, 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.: 1 / Fragment: kinase domain / Mutation: R664E
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-IIW / 6-bromanyl-~{N}-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-5-methanoyl-1-(2-morpholin-4-ylethyl)pyrrolo[3,2-b]pyridine-3-carboxamide


Mass: 556.412 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26BrN7O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 234 / 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: 2.23 Å3/Da / Density % sol: 44.88 %
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: May 24, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.587 Å / Relative weight: 1
ReflectionResolution: 1.987→42.762 Å / Num. obs: 21010 / % possible obs: 99.13 % / Redundancy: 6.7 % / CC1/2: 0.982 / Rrim(I) all: 0.2297 / Net I/σ(I): 7.29
Reflection shellResolution: 1.987→2.058 Å / Redundancy: 4.3 % / Mean I/σ(I) obs: 3.28 / Num. unique obs: 1959 / CC1/2: 0.835 / % possible all: 92.71

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Processing

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

7wct


Resolution: 1.987→42.762 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.42 / Phase error: 19.11 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.196 1050 5 %
Rwork0.1616 19955 -
obs0.1633 21005 99.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 87.9 Å2 / Biso mean: 28.5586 Å2 / Biso min: 13.29 Å2
Refinement stepCycle: final / Resolution: 1.987→42.762 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2352 0 69 234 2655
Biso mean--36.93 36.77 -
Num. residues----300
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0162474
X-RAY DIFFRACTIONf_angle_d1.5683358
X-RAY DIFFRACTIONf_chiral_restr0.083355
X-RAY DIFFRACTIONf_plane_restr0.009434
X-RAY DIFFRACTIONf_dihedral_angle_d14.794939
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.987-2.09170.25761730.1884269895
2.0917-2.22280.21191510.1649283099
2.2228-2.39440.21581320.15832870100
2.3944-2.63530.20541570.16832860100
2.6353-3.01660.22181570.17282865100
3.0166-3.80020.18461470.15862880100
3.8002-42.7620.16381330.15172952100
Refinement TLS params.Method: refined / Origin x: 205.6138 Å / Origin y: 9.3991 Å / Origin z: 133.5693 Å
111213212223313233
T0.1908 Å2-0.0128 Å20.0139 Å2-0.1973 Å20.0012 Å2--0.1935 Å2
L0.5516 °2-0.1625 °20.3932 °2-0.5002 °2-0.2058 °2--0.6576 °2
S0.0089 Å °0.0034 Å °0.0122 Å °-0.0429 Å °-0.0301 Å °-0.0081 Å °0.035 Å °-0.0019 Å °0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA453 - 752
2X-RAY DIFFRACTION1allA800
3X-RAY DIFFRACTION1allA900 - 1002
4X-RAY DIFFRACTION1allS1 - 234

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