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- PDB-6v9c: Crystal structure of FGFR4 kinase domain in complex with covalent... -

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Basic information

Entry
Database: PDB / ID: 6v9c
TitleCrystal structure of FGFR4 kinase domain in complex with covalent inhibitor
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / tyrosine Kinase inhibitor / covalent inhibitor / FGFR / kinase / 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 / positive regulation of DNA biosynthetic process / PI-3K cascade:FGFR4 ...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 / positive regulation of DNA biosynthetic process / PI-3K cascade:FGFR4 / fibroblast growth factor binding / 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 / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / glucose homeostasis / cell migration / PIP3 activates AKT signaling / heparin binding / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein autophosphorylation / receptor complex / positive regulation of ERK1 and ERK2 cascade / 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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase); domain 1 / 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-QS7 / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsLiu, J. / Liu, H.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of Selective, Covalent FGFR4 Inhibitors with Antitumor Activity in Models of Hepatocellular Carcinoma.
Authors: Liu, H. / Niu, D. / Tham Sjin, R.T. / Dubrovskiy, A. / Zhu, Z. / McDonald, J.J. / Fahnoe, K. / Wang, Z. / Munson, M. / Scholte, A. / Barrague, M. / Fitzgerald, M. / Liu, J. / Kothe, M. / ...Authors: Liu, H. / Niu, D. / Tham Sjin, R.T. / Dubrovskiy, A. / Zhu, Z. / McDonald, J.J. / Fahnoe, K. / Wang, Z. / Munson, M. / Scholte, A. / Barrague, M. / Fitzgerald, M. / Liu, J. / Kothe, M. / Sun, F. / Murtie, J. / Ge, J. / Rocnik, J. / Harvey, D. / Ospina, B. / Perron, K. / Zheng, G. / Shehu, E. / D'Agostino, L.A.
History
DepositionDec 13, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 20, 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

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5804
Polymers33,8671
Non-polymers7123
Water2,972165
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.067, 58.670, 60.747
Angle α, β, γ (deg.)90.000, 97.570, 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: 33867.207 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4, JTK2, TKF / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P22455, receptor protein-tyrosine kinase
#2: Chemical ChemComp-QS7 / N-[(3R,4S)-4-{[6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}oxolan-3-yl]prop-2-enamide


Mass: 520.365 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23Cl2N5O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 165 / 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: 2.3 Å3/Da / Density % sol: 46.45 %
Crystal growTemperature: 277 K / Method: batch mode
Details: 100 mM Bis-Tris pH 5.5, 14% (w/v) polyethylene glycol 3,350, 200 mM lithium sulfate and 2% (w/v) glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: OXFORD SAPPHIRE CCD / Detector: CCD / Date: Jun 20, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→42.02 Å / Num. obs: 24253 / % possible obs: 98.6 % / Redundancy: 3.3 % / Biso Wilson estimate: 32.17 Å2 / Rmerge(I) obs: 0.049 / Net I/σ(I): 13.2
Reflection shellResolution: 1.94→1.99 Å / Rmerge(I) obs: 0.56 / Num. unique obs: 1540

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
Aimlessdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3OXZ

3oxz


Resolution: 1.9→42.02 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.919 / SU R Cruickshank DPI: 0.154 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.157 / SU Rfree Blow DPI: 0.137 / SU Rfree Cruickshank DPI: 0.136
RfactorNum. reflection% reflectionSelection details
Rfree0.227 1231 5.09 %RANDOM
Rwork0.199 ---
obs0.201 24186 99.1 %-
Displacement parametersBiso max: 121.47 Å2 / Biso mean: 37.4 Å2 / Biso min: 18.45 Å2
Baniso -1Baniso -2Baniso -3
1--0.0989 Å20 Å2-1.187 Å2
2---0.5259 Å20 Å2
3---0.6247 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 1.9→42.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2210 0 45 165 2420
Biso mean--36.13 45.29 -
Num. residues----279
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d792SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes378HARMONIC5
X-RAY DIFFRACTIONt_it2310HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion279SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2752SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2310HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg3133HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion3.13
X-RAY DIFFRACTIONt_other_torsion15.92
LS refinement shellResolution: 1.9→1.92 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3535 23 4.75 %
Rwork0.3143 461 -
all0.3163 484 -
obs--81.09 %
Refinement TLS params.Method: refined / Origin x: 12.5204 Å / Origin y: 3.938 Å / Origin z: 13.1305 Å
111213212223313233
T0.0599 Å2-0.0592 Å2-0.0305 Å2-0.0477 Å20.0254 Å2--0.0504 Å2
L0.5235 °2-0.5356 °20.5046 °2-1.0159 °2-0.3452 °2--1.4389 °2
S-0.0481 Å °0.1297 Å °0.0657 Å °-0.0022 Å °-0.0475 Å °-0.0459 Å °-0.0009 Å °0.0525 Å °0.0956 Å °
Refinement TLS groupSelection details: { A|453 - A|801 }

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