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- PDB-8udt: The X-RAY co-crystal structure of human FGFR3 and KIN-3248 -

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Basic information

Entry
Database: PDB / ID: 8udt
TitleThe X-RAY co-crystal structure of human FGFR3 and KIN-3248
ComponentsFibroblast growth factor receptor 3
KeywordsTRANSFERASE/INHIBITOR / FGFR inhibitor / Covalent Drug / KIN-3248 / alteration / mutation / structure-based drug design / kinase inhibitor / signaling / proliferation / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


t(4;14) translocations of FGFR3 / negative regulation of developmental growth / fibroblast growth factor receptor apoptotic signaling pathway / Signaling by FGFR3 fusions in cancer / bone maturation / chondrocyte proliferation / endochondral bone growth / FGFR3b ligand binding and activation / Signaling by activated point mutants of FGFR3 / FGFR3c ligand binding and activation ...t(4;14) translocations of FGFR3 / negative regulation of developmental growth / fibroblast growth factor receptor apoptotic signaling pathway / Signaling by FGFR3 fusions in cancer / bone maturation / chondrocyte proliferation / endochondral bone growth / FGFR3b ligand binding and activation / Signaling by activated point mutants of FGFR3 / FGFR3c ligand binding and activation / Phospholipase C-mediated cascade; FGFR3 / endochondral ossification / positive regulation of phospholipase activity / bone morphogenesis / positive regulation of tyrosine phosphorylation of STAT protein / PI-3K cascade:FGFR3 / bone mineralization / fibroblast growth factor binding / PI3K Cascade / cell surface receptor signaling pathway via JAK-STAT / fibroblast growth factor receptor signaling pathway / chondrocyte differentiation / SHC-mediated cascade:FGFR3 / transport vesicle / FRS-mediated FGFR3 signaling / Signaling by FGFR3 in disease / skeletal system development / Negative regulation of FGFR3 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 / Constitutive Signaling by Aberrant PI3K in Cancer / MAPK cascade / cell-cell signaling / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / positive regulation of cell population proliferation / cell surface / endoplasmic reticulum / Golgi apparatus / extracellular region / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
Fibroblast growth factor receptor 3 transmembrane domain / 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 ...Fibroblast growth factor receptor 3 transmembrane domain / 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 / 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
D-MALATE / : / Fibroblast growth factor receptor 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.829 Å
AuthorsTyhonas, J.S. / Arnold, L.D. / Cox, J. / Franovic, A. / Gardiner, E. / Grandinetti, K. / Kania, R. / Kanouni, T. / Lardy, M. / Li, C. ...Tyhonas, J.S. / Arnold, L.D. / Cox, J. / Franovic, A. / Gardiner, E. / Grandinetti, K. / Kania, R. / Kanouni, T. / Lardy, M. / Li, C. / Martin, E.S. / Miller, N. / Mohan, A. / Murphy, E.A. / Perez, M. / Soroceanu, L. / Timple, N. / Uryu, S. / Womble, S. / Kaldor, S.W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations.
Authors: Tyhonas, J.S. / Arnold, L.D. / Cox, J.M. / Franovic, A. / Gardiner, E. / Grandinetti, K. / Kania, R. / Kanouni, T. / Lardy, M. / Li, C. / Martin, E.S. / Miller, N. / Mohan, A. / Murphy, E.A. ...Authors: Tyhonas, J.S. / Arnold, L.D. / Cox, J.M. / Franovic, A. / Gardiner, E. / Grandinetti, K. / Kania, R. / Kanouni, T. / Lardy, M. / Li, C. / Martin, E.S. / Miller, N. / Mohan, A. / Murphy, E.A. / Perez, M. / Soroceanu, L. / Timple, N. / Uryu, S. / Womble, S. / Kaldor, S.W.
History
DepositionSep 29, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 6, 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 3
B: Fibroblast growth factor receptor 3
C: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,0718
Polymers101,2263
Non-polymers1,8455
Water2,162120
1
A: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5364
Polymers33,7421
Non-polymers7943
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2682
Polymers33,7421
Non-polymers5261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2682
Polymers33,7421
Non-polymers5261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.98, 160.44, 179.163
Angle α, β, γ (deg.)90, 90, 90
Int Tables number23
Space group name H-MI222

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Components

#1: Protein Fibroblast growth factor receptor 3 / FGFR-3


Mass: 33742.016 Da / Num. of mol.: 3 / Fragment: kinase domain / Mutation: residues 572-585 replaced by Ser-Gly
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR3, JTK4 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P22607, receptor protein-tyrosine kinase
#2: Chemical ChemComp-MLT / D-MALATE / (2R)-2-HYDROXYBUTANEDIOIC ACID / 2-HYDROXY-SUCCINIC ACID


Mass: 134.087 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H6O5
#3: Chemical ChemComp-WGF / 3-[(1-cyclopropyl-4,6-difluoro-1H-benzimidazol-5-yl)ethynyl]-1-[(3R,5R)-5-(methoxymethyl)-1-propanoylpyrrolidin-3-yl]-5-(methylamino)-1H-pyrazole-4-carboxamide / KIN-3248


Mass: 525.550 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C26H29F2N7O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 120 / 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: 3.19 Å3/Da / Density % sol: 61.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.20 M DL-Malic acid pH 5.00, 18.00 % (w/v) PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jul 27, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.83→33.29 Å / Num. obs: 31351 / % possible obs: 100 % / Redundancy: 28.1 % / Biso Wilson estimate: 99.71 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.12 / Rpim(I) all: 0.02 / Rrim(I) all: 0.12 / Net I/σ(I): 19.1
Reflection shellResolution: 2.83→2.93 Å / Redundancy: 29.2 % / Rmerge(I) obs: 1.75 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 3088 / CC1/2: 0.9 / Rpim(I) all: 0.33 / Rrim(I) all: 1.78 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROC1.1.7data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.829→33.29 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.908 / Cross valid method: THROUGHOUT / SU R Blow DPI: 1.065 / SU Rfree Blow DPI: 0.359
RfactorNum. reflection% reflectionSelection details
Rfree0.274 1548 -RANDOM
Rwork0.2623 ---
obs0.2629 31351 100 %-
Displacement parametersBiso mean: 107.42 Å2
Baniso -1Baniso -2Baniso -3
1-16.8081 Å20 Å20 Å2
2---22.0242 Å20 Å2
3---5.2161 Å2
Refine analyzeLuzzati coordinate error obs: 0.49 Å
Refinement stepCycle: LAST / Resolution: 2.829→33.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6769 0 132 120 7021
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00513887HARMONIC6
X-RAY DIFFRACTIONt_angle_deg0.7525148HARMONIC5
X-RAY DIFFRACTIONt_dihedral_angle_d4182SINUSOIDAL10
X-RAY DIFFRACTIONt_gen_planes2142HARMONIC8
X-RAY DIFFRACTIONt_it7054HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion874SEMIHARMONIC5
X-RAY DIFFRACTIONt_utility_distance1HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact11341SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.17
X-RAY DIFFRACTIONt_other_torsion14.48
LS refinement shellResolution: 2.83→2.85 Å
RfactorNum. reflection% reflection
Rfree0.3846 25 -
Rwork0.3218 --
obs0.3243 628 100 %
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)
13.43620.9396-2.0610-0.64483.34340.0331-0.0349-0.26-0.03490.0506-0.473-0.26-0.473-0.0837-0.15830.0197-0.0189-0.0869-0.0073-0.191827.869523.8767-6.4266
23.12772.9104-0.87350.873-0.32033.41540.23170.0992-0.21290.0992-0.1891-0.4561-0.2129-0.4561-0.0426-0.18690.0263-0.01750.0385-0.0745-0.210845.202331.890653.144
32.25232.9104-1.26192.0463-2.60823.89390.241-0.20740.0896-0.2074-0.2125-0.54420.0896-0.5442-0.0284-0.194-0.1520.0611-0.1117-0.0526-0.159120.57518.00941.3379
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|457 - A|756 }A457 - 756
2X-RAY DIFFRACTION2{ B|458 - B|754 }B458 - 754
3X-RAY DIFFRACTION3{ C|458 - C|758 }C458 - 758

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