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- PDB-8udv: The X-RAY co-crystal structure of human FGFR3 V555M and Compound 17 -

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Basic information

Entry
Database: PDB / ID: 8udv
TitleThe X-RAY co-crystal structure of human FGFR3 V555M and Compound 17
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


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: 2.348 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
C: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,62914
Polymers101,3223
Non-polymers2,30711
Water6,720373
1
A: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5865
Polymers33,7741
Non-polymers8124
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4904
Polymers33,7741
Non-polymers7163
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5525
Polymers33,7741
Non-polymers7784
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)170.664, 54.513, 128.718
Angle α, β, γ (deg.)90, 120.22, 90
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1001-

SO4

21B-801-

SO4

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Components

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


Mass: 33774.078 Da / Num. of mol.: 3 / Fragment: kinase domain
Mutation: V555M and residues 572-585 (Uniprot numbering) 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): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P22607, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#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.: 3 / Source method: obtained synthetically / Formula: C26H30ClN7O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 373 / 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: 2.76 Å3/Da / Density % sol: 55.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.10 M BIS-TRIS/HCl pH 6.50, 0.20 M (NH4)2SO4, 25.00 % (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 16, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.348→34.74 Å / Num. obs: 42440 / % possible obs: 98.3 % / Redundancy: 2.8 % / Biso Wilson estimate: 37.88 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.07 / Rrim(I) all: 0.12 / Net I/σ(I): 8.8
Reflection shellResolution: 2.348→2.43 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.64 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 4114 / CC1/2: 0.47 / Rpim(I) all: 0.49 / Rrim(I) all: 0.81 / % possible all: 96.2

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROC1.1.7data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.348→34.74 Å / Cor.coef. Fo:Fc: 0.903 / Cor.coef. Fo:Fc free: 0.882 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.411 / SU Rfree Blow DPI: 0.252
RfactorNum. reflection% reflectionSelection details
Rfree0.2612 2148 -RANDOM
Rwork0.2362 ---
obs0.2374 42158 97.6 %-
Displacement parametersBiso mean: 39.38 Å2
Baniso -1Baniso -2Baniso -3
1--2.2682 Å20 Å2-2.0697 Å2
2---8.906 Å20 Å2
3---11.1743 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: LAST / Resolution: 2.348→34.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6544 0 150 373 7067
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00613454HARMONIC3
X-RAY DIFFRACTIONt_angle_deg1.0124369HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4030SINUSOIDAL5
X-RAY DIFFRACTIONt_gen_planes2054HARMONIC5
X-RAY DIFFRACTIONt_it6830HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion850SEMIHARMONIC5
X-RAY DIFFRACTIONt_utility_distance1HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact10685SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.24
X-RAY DIFFRACTIONt_other_torsion13.81
LS refinement shellResolution: 2.35→2.36 Å
RfactorNum. reflection% reflection
Rfree0.3035 54 -
Rwork0.2955 --
obs0.296 844 91.19 %
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)
10.571-0.26430.3030.2228-0.36781.1170.01310.0133-0.00280.0133-0.0066-0.0403-0.0028-0.0403-0.0065-0.02890.00420.0125-0.0647-0.0235-0.0276-41.128624.660129.0983
20.4175-0.1456-0.07771.54160.84290.91960.00330.02980.03230.0298-0.0022-0.08180.0323-0.0818-0.0011-0.07960.00440.0258-0.04230.0183-0.0333-69.604611.950412.3711
30.838-0.22090.42790.10440.30951.3726-0.0263-0.00710.0732-0.00710.07090.04660.07320.0466-0.0445-0.04680.07820.0129-0.0176-0.0118-0.0617-7.860412.00735.4852
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|459 - A|742 }A459 - 742
2X-RAY DIFFRACTION2{ B|455 - B|743 }B455 - 743
3X-RAY DIFFRACTION3{ C|459 - C|742 }C459 - 742

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