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- PDB-7kia: Crystal structure of FGFR2 kinase domain gatekeeper mutant V564F ... -

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Basic information

Entry
Database: PDB / ID: 7kia
TitleCrystal structure of FGFR2 kinase domain gatekeeper mutant V564F in complex with covalent compound 19
ComponentsFibroblast growth factor receptor 2
KeywordsSIGNALING PROTEIN / FGFR kinase domain / FGFR / FGFR2 / FGFR3 / kinase inhibitor / covalent inhibitor / gatekeeper mutant / RTK
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 / lateral sprouting from an epithelium / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / 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 / lateral sprouting from an epithelium / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland development / prostate gland morphogenesis / otic vesicle formation / regulation of smooth muscle cell differentiation / regulation of morphogenesis of a branching structure / orbitofrontal cortex development / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / embryonic organ morphogenesis / branching morphogenesis of a nerve / endochondral bone growth / morphogenesis of embryonic epithelium / bud elongation involved in lung branching / epidermis morphogenesis / positive regulation of epithelial cell proliferation involved in lung morphogenesis / reproductive structure development / limb bud formation / membranous septum morphogenesis / gland morphogenesis / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / embryonic digestive tract morphogenesis / lung lobe morphogenesis / mesenchymal cell differentiation / positive regulation of phospholipase activity / epithelial cell proliferation involved in salivary gland morphogenesis / mesenchymal cell proliferation involved in lung development / branching involved in prostate gland morphogenesis / FGFR2b ligand binding and activation / branching involved in labyrinthine layer morphogenesis / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / Phospholipase C-mediated cascade; FGFR2 / regulation of osteoblast proliferation / branching involved in salivary gland morphogenesis / embryonic pattern specification / pyramidal neuron development / lung-associated mesenchyme development / embryonic cranial skeleton morphogenesis / outflow tract septum morphogenesis / regulation of smoothened signaling pathway / mesodermal cell differentiation / bone morphogenesis / digestive tract development / odontogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / skeletal system morphogenesis / inner ear morphogenesis / lung alveolus development / organ growth / hair follicle morphogenesis / Signaling by FGFR2 IIIa TM / ventricular cardiac muscle tissue morphogenesis / regulation of osteoblast differentiation / PI-3K cascade:FGFR2 / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / prostate epithelial cord elongation / bone mineralization / midbrain development / fibroblast growth factor binding / positive regulation of cell division / PI3K Cascade / excitatory synapse / epithelial to mesenchymal transition / cell fate commitment / fibroblast growth factor receptor signaling pathway / positive regulation of Wnt signaling pathway / negative regulation of keratinocyte proliferation / embryonic organ development / fibroblast growth factor receptor activity / cellular response to transforming growth factor beta stimulus / regulation of ERK1 and ERK2 cascade / SHC-mediated cascade:FGFR2 / positive regulation of cardiac muscle cell proliferation / positive regulation of vascular associated smooth muscle cell proliferation / FRS-mediated FGFR2 signaling / positive regulation of cell cycle / cellular response to retinoic acid / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / positive regulation of epithelial cell proliferation / animal organ morphogenesis / post-embryonic development / Negative regulation of FGFR2 signaling / lung development / peptidyl-tyrosine phosphorylation / receptor protein-tyrosine kinase / bone development / 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. ...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 / 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 / Transferase(Phosphotransferase); domain 1 / 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
CITRATE ANION / Chem-WFD / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.22 Å
AuthorsKe, J. / Wibowo, A.S. / Carter, J.J. / Larsen, N.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3.
Authors: Brawn, R.A. / Cook, A. / Omoto, K. / Ke, J. / Karr, C. / Colombo, F. / Virrankoski, M. / Prajapati, S. / Reynolds, D. / Bolduc, D.M. / Nguyen, T.V. / Gee, P. / Borrelli, D. / Caleb, B. / ...Authors: Brawn, R.A. / Cook, A. / Omoto, K. / Ke, J. / Karr, C. / Colombo, F. / Virrankoski, M. / Prajapati, S. / Reynolds, D. / Bolduc, D.M. / Nguyen, T.V. / Gee, P. / Borrelli, D. / Caleb, B. / Yao, S. / Irwin, S. / Larsen, N.A. / Selvaraj, A. / Zhao, X. / Ioannidis, S.
History
DepositionOct 23, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 10, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id
Revision 1.2Nov 13, 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

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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)72,0538
Polymers70,6552
Non-polymers1,3976
Water4,017223
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0264
Polymers35,3281
Non-polymers6993
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0264
Polymers35,3281
Non-polymers6993
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)105.980, 117.300, 63.810
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: WFD / End label comp-ID: WFD / Refine code: 4 / Auth seq-ID: 467 - 801 / Label seq-ID: 7

Dom-IDAuth asym-IDLabel asym-ID
1AA - C
2BB - F

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.02345, 0.702223, 0.711571), (0.692307, -0.502077, 0.518296), (0.721222, 0.50478, -0.474379)-44.088268, 64.338814, -2.48915

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Components

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


Mass: 35327.656 Da / Num. of mol.: 2 / Fragment: Kinase domain, residues 461-768 / Mutation: V564F
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-WFD / 1-[4-(4-{4-(4-methylpiperazin-1-yl)-6-[(3-methyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}phenyl)piperidin-1-yl]prop-2-en-1-one


Mass: 486.612 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H34N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-FLC / CITRATE ANION


Mass: 189.100 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H5O7
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 223 / 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: 2.81 Å3/Da / Density % sol: 56.18 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 4 / Details: 12% w/v PEG 8000, 0.1M Sodium Citrate pH 4.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X17B1 / Wavelength: 0.92009 Å
DetectorType: DECTRIS PILATUS3 R CdTe 300K / Detector: PIXEL / Date: Jun 5, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92009 Å / Relative weight: 1
ReflectionResolution: 2.22→58.65 Å / Num. obs: 40121 / % possible obs: 100 % / Redundancy: 7.4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.123 / Rpim(I) all: 0.048 / Rrim(I) all: 0.133 / Net I/σ(I): 9.8 / Num. measured all: 298777 / Scaling rejects: 20
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.22-2.287.81.2422302529360.6360.4731.331.7100
9.93-58.656.50.04834795370.9970.020.05225.599.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0238refinement
XDSdata reduction
Aimless0.7.4data scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3RI1

3ri1


Resolution: 2.22→50.01 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.946 / SU B: 6.154 / SU ML: 0.146 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.234 / ESU R Free: 0.182 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2232 2032 5.1 %RANDOM
Rwork0.1988 ---
obs0.2 38036 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 132.54 Å2 / Biso mean: 48.065 Å2 / Biso min: 22.36 Å2
Baniso -1Baniso -2Baniso -3
1--0.78 Å2-0 Å20 Å2
2--0.4 Å2-0 Å2
3---0.38 Å2
Refinement stepCycle: final / Resolution: 2.22→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4605 0 100 223 4928
Biso mean--58.87 47.7 -
Num. residues----575
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0124841
X-RAY DIFFRACTIONr_angle_refined_deg1.2411.6676549
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4475581
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.09322.642246
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.48815878
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2441530
X-RAY DIFFRACTIONr_chiral_restr0.0920.2602
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023686
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Number: 2291 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
MEDIUM POSITIONAL0.380.5
MEDIUM THERMAL5.732
LS refinement shellResolution: 2.22→2.278 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 159 -
Rwork0.294 2773 -
all-2932 -
obs--100 %

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