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- PDB-8udu: The X-RAY co-crystal structure of human FGFR3 and Compound 17 -

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Basic information

Entry
Database: PDB / ID: 8udu
TitleThe X-RAY co-crystal structure of human FGFR3 and Compound 17
ComponentsFibroblast growth factor receptor 3
KeywordsTRANSFERASE/INHIBITOR / FGFR inhibitor / Covalent Drug / alteration / mutation / structure-based drug design / kinase inhibitor / signaling / proliferation / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


fibroblast growth factor receptor apoptotic signaling pathway / t(4;14) translocations of FGFR3 / negative regulation of developmental growth / 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 ...fibroblast growth factor receptor apoptotic signaling pathway / t(4;14) translocations of FGFR3 / negative regulation of developmental growth / 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 / fibroblast growth factor receptor activity / endochondral ossification / positive regulation of phospholipase activity / bone morphogenesis / PI-3K cascade:FGFR3 / fibroblast growth factor binding / bone mineralization / cell surface receptor signaling pathway via JAK-STAT / PI3K Cascade / fibroblast growth factor receptor signaling pathway / chondrocyte differentiation / SHC-mediated cascade:FGFR3 / FRS-mediated FGFR3 signaling / positive regulation of tyrosine phosphorylation of STAT protein / transport vesicle / Signaling by FGFR3 in disease / skeletal system development / Negative regulation of FGFR3 signaling / receptor protein-tyrosine kinase / Constitutive Signaling by Aberrant PI3K in Cancer / MAPK cascade / PIP3 activates AKT signaling / cell-cell signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / receptor complex / phosphorylation / positive regulation of cell population proliferation / Golgi apparatus / cell surface / endoplasmic reticulum / 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 / Tyrosine protein kinases specific active-site signature. ...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. / 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 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.737 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

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6036
Polymers67,4842
Non-polymers1,1194
Water5,819323
1
A: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3013
Polymers33,7421
Non-polymers5592
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3013
Polymers33,7421
Non-polymers5592
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.7, 69.314, 78.473
Angle α, β, γ (deg.)90, 90.96, 90
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 33742.016 Da / Num. of mol.: 2 / 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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-WIQ / 3-[(6-chloro-1-cyclopropyl-1H-benzimidazol-5-yl)ethynyl]-1-[(3S,5S)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)-1H-pyrazole-4-carboxamide


Mass: 524.014 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H30ClN7O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 323 / Source method: isolated from a natural source / Formula: H2O
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: 2.4 Å3/Da / Density % sol: 48.82 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.10 M Magnesium Chloride, 0.10 M TRIS/HCl pH 8.10, 0.20 M Sodium Chloride, 20.00 % (w/v) PEG 3350

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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: 1.737→34.14 Å / Num. obs: 61639 / % possible obs: 100 % / Redundancy: 14 % / Biso Wilson estimate: 36.77 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.04 / Rpim(I) all: 0.01 / Rrim(I) all: 0.04 / Net I/σ(I): 26.9
Reflection shellResolution: 1.737→1.8 Å / Redundancy: 13.5 % / Rmerge(I) obs: 0.91 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 6122 / CC1/2: 0.9 / Rpim(I) all: 0.26 / Rrim(I) all: 0.95 / % 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: 1.737→34.14 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.932 / SU R Cruickshank DPI: 0.178 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.136 / SU Rfree Blow DPI: 0.124 / SU Rfree Cruickshank DPI: 0.124
RfactorNum. reflection% reflectionSelection details
Rfree0.2558 2972 -RANDOM
Rwork0.2298 ---
obs0.2311 61639 100 %-
Displacement parametersBiso mean: 47.52 Å2
Baniso -1Baniso -2Baniso -3
1-1.2608 Å20 Å23.3368 Å2
2--0.0675 Å20 Å2
3----1.3283 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 1.737→34.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4403 0 76 323 4802
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0089154HARMONIC5
X-RAY DIFFRACTIONt_angle_deg0.7816572HARMONIC5
X-RAY DIFFRACTIONt_dihedral_angle_d2748SINUSOIDAL10
X-RAY DIFFRACTIONt_gen_planes1428HARMONIC8
X-RAY DIFFRACTIONt_it4647HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion575SEMIHARMONIC5
X-RAY DIFFRACTIONt_utility_distance1HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact8121SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.56
X-RAY DIFFRACTIONt_other_torsion12.93
LS refinement shellResolution: 1.74→1.75 Å
RfactorNum. reflection% reflection
Rfree0.2494 56 -
Rwork0.276 --
obs0.2748 1233 100 %
Refinement TLS params.

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)
1-0.0013-0.22140.03540.4134-0.01270.28610.0346-0.07010.0132-0.07010.01970.00060.01320.0006-0.05440.031-0.0167-0.0302-0.03460.04440.012119.0723-1.403631.0634
21.5352-0.0301-0.67280.3415-0.00641.2274-0.0394-0.1285-0.0118-0.12850.057-0.1337-0.0118-0.1337-0.0176-0.02780.0487-0.03160.0144-0.0064-0.028813.126-0.8003-8.7249
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A460 - 759
2X-RAY DIFFRACTION1{ A|* }A1001 - 2001
3X-RAY DIFFRACTION2{ B|* }B459 - 755
4X-RAY DIFFRACTION2{ B|* }B1001 - 2001

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