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- PDB-5o4a: Human FGF in complex with a covalent inhibitor -

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Basic information

Entry
Database: PDB / ID: 5o4a
TitleHuman FGF in complex with a covalent inhibitor
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE / FGFR Fibroblast Growth Factor / covalent inhibition / FGFR Fibroblast Grwth Fctr RTK
Function / homology
Function and homology information


Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification ...Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / cementum mineralization / positive regulation of endothelial cell chemotaxis to fibroblast growth factor / response to sodium phosphate / receptor-receptor interaction / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / auditory receptor cell development / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of parathyroid hormone secretion / chordate embryonic development / mesenchymal cell proliferation / paraxial mesoderm development / FGFR1b ligand binding and activation / fibroblast growth factor receptor activity / branching involved in salivary gland morphogenesis / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / positive regulation of phospholipase activity / lung-associated mesenchyme development / cell projection assembly / phosphatidylinositol-mediated signaling / outer ear morphogenesis / middle ear morphogenesis / embryonic limb morphogenesis / skeletal system morphogenesis / ureteric bud development / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / cardiac muscle cell proliferation / inner ear morphogenesis / midbrain development / fibroblast growth factor binding / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / PI-3K cascade:FGFR1 / regulation of cell differentiation / PI3K Cascade / epithelial to mesenchymal transition / positive regulation of blood vessel endothelial cell migration / fibroblast growth factor receptor signaling pathway / calcium ion homeostasis / chondrocyte differentiation / positive regulation of phospholipase C activity / SHC-mediated cascade:FGFR1 / cell maturation / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR1 signaling / Signaling by FGFR1 in disease / positive regulation of neuron differentiation / NCAM signaling for neurite out-growth / SH2 domain binding / Signal transduction by L1 / skeletal system development / stem cell proliferation / stem cell differentiation / positive regulation of cell differentiation / sensory perception of sound / Negative regulation of FGFR1 signaling / neuron migration / positive regulation of MAP kinase activity / receptor protein-tyrosine kinase / positive regulation of neuron projection development / peptidyl-tyrosine phosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / neuron projection development / MAPK cascade / cell migration / PIP3 activates AKT signaling / heparin binding / gene expression / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / cytoplasmic vesicle / RAF/MAP kinase cascade / protein tyrosine kinase activity / angiogenesis / in utero embryonic development / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / protein phosphorylation / positive regulation of cell population proliferation / negative regulation of transcription by RNA polymerase II / protein homodimerization activity
Similarity search - Function
Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor receptor family / Immunoglobulin / 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 ...Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor receptor family / Immunoglobulin / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-9K8 / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.01 Å
AuthorsDebreczeni, J. / Breed, J. / Mukherjee, H. / Aquila, B. / Kaiser, C. / Tentarelli, S. / Whitty, A. / Grimster, N.
CitationJournal: Org. Biomol. Chem. / Year: 2017
Title: A study of the reactivity of S(VI)-F containing warheads with nucleophilic amino-acid side chains under physiological conditions.
Authors: Mukherjee, H. / Debreczeni, J. / Breed, J. / Tentarelli, S. / Aquila, B. / Dowling, J.E. / Whitty, A. / Grimster, N.P.
History
DepositionMay 26, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 7, 2018Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 1
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,6148
Polymers70,2712
Non-polymers1,3436
Water3,423190
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9015
Polymers35,1351
Non-polymers7664
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7133
Polymers35,1351
Non-polymers5782
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)211.140, 57.270, 66.800
Angle α, β, γ (deg.)90.00, 107.57, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Fibroblast growth factor receptor 1 / / FGFR-1 / Basic fibroblast growth factor receptor 1 / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 ...FGFR-1 / Basic fibroblast growth factor receptor 1 / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / N-sam / Proto-oncogene c-Fgr


Mass: 35135.340 Da / Num. of mol.: 2 / Fragment: UNP residues 458-765
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR / Production host: Escherichia coli (E. coli)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-9K8 / [(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl 4-ethyl-3-fluorosulfonyl-benzoate


Mass: 481.455 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20FN5O7S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 190 / Source method: isolated from a natural source / Formula: H2O

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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: 2.74 Å3/Da / Density % sol: 55.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 18-20% (w/v) PEG8000, 200mM ammonium sulphate, 100mM PCTP pH 6.75 and 20% (v/v) ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92819 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 2.01→63.68 Å / Num. all: 167464 / Num. obs: 50255 / % possible obs: 98.9 % / Redundancy: 3.3 % / Biso Wilson estimate: 49.37 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.03 / Net I/σ(I): 15.1
Reflection shellResolution: 2.01→2.06 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.858 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 12626 / CC1/2: 0.683 / % possible all: 98.9

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.01→63.68 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.921 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.17 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.169 / SU Rfree Blow DPI: 0.138 / SU Rfree Cruickshank DPI: 0.139
RfactorNum. reflection% reflectionSelection details
Rfree0.225 2449 4.87 %RANDOM
Rwork0.217 ---
obs0.217 50253 98.6 %-
Displacement parametersBiso mean: 62.79 Å2
Baniso -1Baniso -2Baniso -3
1-11.9796 Å20 Å2-1.4319 Å2
2---19.2143 Å20 Å2
3---7.2347 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: 1 / Resolution: 2.01→63.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4428 0 86 190 4704
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0114670HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.266361HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1591SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes100HARMONIC2
X-RAY DIFFRACTIONt_gen_planes673HARMONIC5
X-RAY DIFFRACTIONt_it4670HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.28
X-RAY DIFFRACTIONt_other_torsion17.91
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion602SEMIHARMONIC5
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_contact5134SEMIHARMONIC4
LS refinement shellResolution: 2.01→2.06 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.295 180 4.84 %
Rwork0.259 3539 -
all0.261 3719 -
obs--99.54 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.2180.1611-0.48880.3567-0.26040.88940.08180.13010.10310.0001-0.0893-0.0681-0.13070.09450.0075-0.3096-0.0168-0.0189-0.26410.0445-0.304982.0397-1.697318.8523
24.1745-1.12990.41011.02080.47111.05010.25290.51-0.23790.0011-0.2620.06290.04330.02420.0091-0.28390.0189-0.0136-0.3050.0197-0.334635.31192.035514.5472
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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