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- PDB-9vlm: The X-RAY co-crystal structure of human FGFR2 and covalent inhibi... -

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Basic information

Entry
Database: PDB / ID: 9vlm
TitleThe X-RAY co-crystal structure of human FGFR2 and covalent inhibitor 10a
ComponentsFibroblast growth factor receptor 2
KeywordsTRANSFERASE / FGFR2
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 / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland 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 / 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 / regulation of morphogenesis of a branching structure / orbitofrontal cortex development / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / branching morphogenesis of a nerve / morphogenesis of embryonic epithelium / embryonic organ morphogenesis / bud elongation involved in lung branching / endochondral bone growth / epidermis morphogenesis / reproductive structure development / positive regulation of epithelial cell proliferation involved in lung morphogenesis / limb bud formation / embryonic digestive tract morphogenesis / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / membranous septum morphogenesis / gland morphogenesis / mesenchymal cell differentiation / epithelial cell proliferation involved in salivary gland morphogenesis / positive regulation of phospholipase activity / mesenchymal cell proliferation involved in lung development / FGFR2b ligand binding and activation / lung lobe morphogenesis / branching involved in prostate gland morphogenesis / 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 / fibroblast growth factor receptor activity / branching involved in salivary gland morphogenesis / embryonic cranial skeleton morphogenesis / embryonic pattern specification / lung-associated mesenchyme development / pyramidal neuron development / regulation of smoothened signaling pathway / outflow tract septum morphogenesis / bone morphogenesis / mesodermal cell differentiation / digestive tract development / odontogenesis / ureteric bud development / positive regulation of mesenchymal cell proliferation / skeletal system morphogenesis / organ growth / hair follicle morphogenesis / Signaling by FGFR2 IIIa TM / inner ear morphogenesis / lung alveolus development / prostate epithelial cord elongation / ventricular cardiac muscle tissue morphogenesis / regulation of osteoblast differentiation / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / PI-3K cascade:FGFR2 / midbrain development / bone mineralization / positive regulation of cell division / fibroblast growth factor binding / fibroblast growth factor receptor signaling pathway / PI3K Cascade / epithelial to mesenchymal transition / negative regulation of keratinocyte proliferation / cell fate commitment / embryonic organ development / cellular response to transforming growth factor beta stimulus / regulation of ERK1 and ERK2 cascade / positive regulation of cardiac muscle cell proliferation / positive regulation of Wnt signaling pathway / SHC-mediated cascade:FGFR2 / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to retinoic acid / FRS-mediated FGFR2 signaling / peptidyl-tyrosine phosphorylation / epithelial cell differentiation / Signaling by FGFR2 in disease / positive regulation of cell cycle / lung development / axonogenesis / excitatory synapse / positive regulation of epithelial cell proliferation / animal organ morphogenesis / post-embryonic development / Negative regulation of FGFR2 signaling / receptor protein-tyrosine kinase / bone development / Constitutive Signaling by Aberrant PI3K in Cancer / protein autophosphorylation
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 / 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: 2.26 Å
AuthorsChen, X.J. / Liu, X.R. / Zhang, L. / Chen, Y.H.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82202920 China
National Natural Science Foundation of China (NSFC)82172654 China
CitationJournal: J.Med.Chem. / Year: 2026
Title: Structure-Based Design of 4-(1-Methyl-1 H -indol-3-yl)pyrimidin-2-amine Derivatives as the First Covalent FGFR3 Selective Inhibitors.
Authors: Zhu, W. / Chen, X. / Li, X. / Lin, J. / Lin, X. / Liu, X. / Deng, W. / Song, X. / Tu, Z. / Patterson, A.V. / Smaill, J.B. / Chen, Y. / Lu, X.
History
DepositionJun 25, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0May 6, 2026Provider: 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)70,7506
Polymers69,4942
Non-polymers1,2564
Water2,198122
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3753
Polymers34,7471
Non-polymers6282
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3753
Polymers34,7471
Non-polymers6282
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.982, 47.563, 108.904
Angle α, β, γ (deg.)90.00, 101.57, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 34747.113 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-A1ESP / ~{N}-[3-[2-[[3-[2-(dimethylamino)ethylsulfamoylmethyl]phenyl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]propanamide


Mass: 535.661 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N7O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 46.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 22% (w/v) PEG 8000, and 0.1 M Tris-HCl, pH 8.0

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 13, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.26→106.69 Å / Num. obs: 28979 / % possible obs: 96.53 % / Redundancy: 3.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.05818 / Net I/σ(I): 14.63
Reflection shellResolution: 2.263→2.343 Å / Rmerge(I) obs: 0.6236 / Mean I/σ(I) obs: 2.29 / Num. unique obs: 2845 / CC1/2: 0.769

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
autoPROCdata reduction
autoPROCdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.26→53.34 Å / SU ML: 0.28 / Cross valid method: NONE / σ(F): 1.34 / Phase error: 25.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2537 1362 4.72 %
Rwork0.207 --
obs0.2092 28871 96.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.26→53.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4406 0 88 122 4616
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034620
X-RAY DIFFRACTIONf_angle_d0.7656249
X-RAY DIFFRACTIONf_dihedral_angle_d9.455626
X-RAY DIFFRACTIONf_chiral_restr0.042673
X-RAY DIFFRACTIONf_plane_restr0.006795
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.26-2.340.29531610.25472682X-RAY DIFFRACTION97
2.34-2.440.31051310.25052857X-RAY DIFFRACTION100
2.44-2.550.29911290.24852811X-RAY DIFFRACTION100
2.55-2.680.30621610.24342806X-RAY DIFFRACTION100
2.68-2.850.34211380.24162838X-RAY DIFFRACTION100
2.85-3.070.25461350.21772824X-RAY DIFFRACTION100
3.07-3.380.26191340.2162872X-RAY DIFFRACTION100
3.38-3.860.2636830.19522196X-RAY DIFFRACTION78
3.91-4.870.20341490.17212663X-RAY DIFFRACTION99
4.87-53.340.22761410.19022960X-RAY DIFFRACTION100

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