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- PDB-8u1f: FGFR2 Kinase Domain Bound to Irreversible Inhibitor Cmpd 10 -

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Basic information

Entry
Database: PDB / ID: 8u1f
TitleFGFR2 Kinase Domain Bound to Irreversible Inhibitor Cmpd 10
ComponentsFibroblast growth factor receptor 2
KeywordsTransferase/Inhibitor / Inhibitor Kinase / ONCOPROTEIN / Transferase-Inhibitor complex
Function / homology
Function and homology information


Signaling by FGFR2 amplification mutants / Signaling by FGFR2 fusions / fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell / fibroblast growth factor receptor signaling pathway involved in hemopoiesis / fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / lateral sprouting from an epithelium / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development ...Signaling by FGFR2 amplification mutants / Signaling by FGFR2 fusions / fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell / fibroblast growth factor receptor signaling pathway involved in hemopoiesis / fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / lateral sprouting from an epithelium / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland development / otic vesicle formation / prostate gland morphogenesis / regulation of smooth muscle cell differentiation / orbitofrontal cortex development / regulation of morphogenesis of a branching structure / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / branching morphogenesis of a nerve / embryonic organ morphogenesis / endochondral bone growth / morphogenesis of embryonic epithelium / epidermis morphogenesis / bud elongation involved in lung branching / positive regulation of epithelial cell proliferation involved in lung morphogenesis / pyramidal neuron development / membranous septum morphogenesis / reproductive structure development / limb bud formation / lung lobe morphogenesis / gland morphogenesis / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / embryonic digestive tract morphogenesis / epithelial cell proliferation involved in salivary gland morphogenesis / mesenchymal cell differentiation / branching involved in prostate gland morphogenesis / mesenchymal cell proliferation involved in lung development / branching involved in labyrinthine layer morphogenesis / FGFR2b ligand binding and activation / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / regulation of osteoblast proliferation / Phospholipase C-mediated cascade; FGFR2 / fibroblast growth factor receptor activity / embryonic pattern specification / branching involved in salivary gland morphogenesis / outflow tract septum morphogenesis / positive regulation of phospholipase activity / lung-associated mesenchyme development / mesodermal cell differentiation / regulation of smoothened signaling pathway / embryonic cranial skeleton morphogenesis / digestive tract development / bone morphogenesis / skeletal system morphogenesis / odontogenesis / positive regulation of mesenchymal cell proliferation / ventricular cardiac muscle tissue morphogenesis / ureteric bud development / regulation of osteoblast differentiation / Signaling by FGFR2 IIIa TM / midbrain development / organ growth / inner ear morphogenesis / hair follicle morphogenesis / lung alveolus development / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / fibroblast growth factor binding / PI-3K cascade:FGFR2 / bone mineralization / prostate epithelial cord elongation / positive regulation of cell division / excitatory synapse / PI3K Cascade / positive regulation of Wnt signaling pathway / negative regulation of keratinocyte proliferation / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / cell fate commitment / embryonic organ development / positive regulation of cell cycle / SHC-mediated cascade:FGFR2 / cellular response to retinoic acid / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR2 signaling / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to transforming growth factor beta stimulus / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / regulation of ERK1 and ERK2 cascade / post-embryonic development / positive regulation of epithelial cell proliferation / Negative regulation of FGFR2 signaling / animal organ morphogenesis / lung development / bone development / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer
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
: / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.33 Å
AuthorsValverde, R. / Foster, L.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2024
Title: Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.
Authors: Schonherr, H. / Ayaz, P. / Taylor, A.M. / Casaletto, J.B. / Toure, B.B. / Moustakas, D.T. / Hudson, B.M. / Valverde, R. / Zhao, S. / O'Hearn, P.J. / Foster, L. / Sharon, D.A. / Garfinkle, S. ...Authors: Schonherr, H. / Ayaz, P. / Taylor, A.M. / Casaletto, J.B. / Toure, B.B. / Moustakas, D.T. / Hudson, B.M. / Valverde, R. / Zhao, S. / O'Hearn, P.J. / Foster, L. / Sharon, D.A. / Garfinkle, S. / Giordanetto, F. / Lescarbeau, A. / Kurukulasuriya, R. / Gerami-Moayed, N. / Maglic, D. / Bruderek, K. / Naik, G. / Gunaydin, H. / Mader, M.M. / Boezio, A.A. / McLean, T.H. / Chen, R. / Wang, Y. / Shaw, D.E. / Watters, J. / Bergstrom, D.A.
History
DepositionAug 31, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 14, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,4196
Polymers72,2432
Non-polymers1,1754
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.513, 88.280, 129.132
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Fibroblast growth factor receptor 2 / FGFR-2 / K-sam / KGFR / Keratinocyte growth factor receptor


Mass: 36121.621 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR2, BEK, KGFR, KSAM / Production host: Escherichia coli (E. coli)
References: UniProt: P21802, receptor protein-tyrosine kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-UIM / N-[4-(4-amino-7-methyl-5-{4-[(4-methylpyrimidin-2-yl)oxy]phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-methylpropanamide


Mass: 493.560 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H27N7O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
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: 2.47 Å3/Da / Density % sol: 50.12 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 0.1 M Tris pH 8, 18% PEG K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.9793 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 16, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 3.06→52.11 Å / Num. obs: 14247 / % possible obs: 97.1 % / Redundancy: 5.5 % / Biso Wilson estimate: 69.68 Å2 / CC1/2: 0.97 / Rmerge(I) obs: 0.136 / Net I/σ(I): 4.5
Reflection shellResolution: 3.06→3.14 Å / Num. unique obs: 6280 / CC1/2: 0.353

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROCdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.33→52.11 Å / SU ML: 0.4537 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 30.1087
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2954 540 4.93 %
Rwork0.2675 10419 -
obs0.2689 10959 99.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 65.22 Å2
Refinement stepCycle: LAST / Resolution: 3.33→52.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4333 0 85 0 4418
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00334515
X-RAY DIFFRACTIONf_angle_d0.70916101
X-RAY DIFFRACTIONf_chiral_restr0.0408661
X-RAY DIFFRACTIONf_plane_restr0.0176771
X-RAY DIFFRACTIONf_dihedral_angle_d5.8078592
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.33-3.660.40021450.3322534X-RAY DIFFRACTION99.3
3.66-4.190.28661280.27092566X-RAY DIFFRACTION99.59
4.19-5.280.28521390.25252592X-RAY DIFFRACTION99.74
5.28-52.110.25911280.24992727X-RAY DIFFRACTION99.58

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