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- PDB-9cd5: FGFR1 Kinase Domain Soak with Inhibitor TYRA-300 -

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Basic information

Entry
Database: PDB / ID: 9cd5
TitleFGFR1 Kinase Domain Soak with Inhibitor TYRA-300
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Transferase / Inhibitor / Cancer / Achondroplasia / FGFR3 / FGFR / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway ...Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / cementum mineralization / vitamin D3 metabolic process / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / response to sodium phosphate / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / receptor-receptor interaction / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of phospholipase activity / chordate embryonic development / auditory receptor cell development / positive regulation of parathyroid hormone secretion / mesenchymal cell proliferation / paraxial mesoderm development / FGFR1b ligand binding and activation / regulation of postsynaptic density assembly / Signaling by activated point mutants of FGFR1 / fibroblast growth factor receptor activity / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / branching involved in salivary gland morphogenesis / Phospholipase C-mediated cascade: FGFR1 / lung-associated mesenchyme development / cell projection assembly / outer ear morphogenesis / embryonic limb morphogenesis / positive regulation of endothelial cell chemotaxis / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / ureteric bud development / middle ear morphogenesis / skeletal system morphogenesis / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / midbrain development / fibroblast growth factor binding / positive regulation of MAP kinase activity / regulation of cell differentiation / PI3K Cascade / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / chondrocyte differentiation / cardiac muscle cell proliferation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / positive regulation of cardiac muscle cell proliferation / cell maturation / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / peptidyl-tyrosine phosphorylation / stem cell proliferation / Signal transduction by L1 / skeletal system development / stem cell differentiation / positive regulation of cell differentiation / Negative regulation of FGFR1 signaling / sensory perception of sound / positive regulation of neuron projection development / receptor protein-tyrosine kinase / neuron migration / neuron projection development / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / MAPK cascade / heparin binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / cytoplasmic vesicle / protein tyrosine kinase activity / angiogenesis / gene expression / in utero embryonic development / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / postsynapse / positive regulation of MAPK cascade / positive regulation of cell population proliferation / glutamatergic synapse
Similarity search - Function
Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor receptor family / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain ...Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor receptor family / Immunoglobulin / 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 / 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 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.939 Å
AuthorsHoffman, I.H. / Nelson, K.J. / Rideout, M.C. / Frye, C. / Bensen, D.C. / Hudkins, R.L.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of TYRA-300: First Oral Selective FGFR3 Inhibitor for the Treatment of Urothelial Cancers and Achondroplasia.
Authors: Hudkins, R.L. / Allen, E. / Balcer, A. / Hoffman, I.D. / Iyer, S. / Neal, M. / Nelson, K.J. / Rideout, M. / Ye, Q. / Starrett, J.H. / Patel, P. / Harris, T. / Swanson, R.V. / Bensen, D.C.
History
DepositionJun 24, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 1
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,71120
Polymers70,1572
Non-polymers2,55418
Water1,08160
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,62613
Polymers35,0781
Non-polymers1,54812
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0847
Polymers35,0781
Non-polymers1,0066
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)206.030, 57.614, 65.694
Angle α, β, γ (deg.)90.000, 107.185, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-909-

SO4

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21A

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: LEU / Beg label comp-ID: LEU / End auth comp-ID: GLN / End label comp-ID: GLN / Auth asym-ID: A / Label asym-ID: A / Auth seq-ID: 465 - 764 / Label seq-ID: 8 - 307

Dom-ID
1
2

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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Components

#1: Protein Fibroblast growth factor receptor 1 / FGFR-1 / Basic fibroblast growth factor receptor 1 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 ...FGFR-1 / Basic fibroblast growth factor receptor 1 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / N-sam / Proto-oncogene c-Fgr


Mass: 35078.285 Da / Num. of mol.: 2 / Mutation: C488A, C584S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR / Production host: Escherichia coli (E. coli)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-A1AV2 / (3P)-5-[(1R)-1-(3,5-dichloropyridin-4-yl)ethoxy]-3-{6-[6-(methanesulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl]pyridin-3-yl}-1H-indazole


Mass: 559.467 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H24Cl2N6O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 60 / 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: 2.65 Å3/Da / Density % sol: 53.6 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 25%P8K, 25% EG, 0.25M AS, 0.1MPCTP pH7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.54184 Å
DetectorType: APEX II CCD / Detector: CCD / Date: Oct 29, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54184 Å / Relative weight: 1
ReflectionResolution: 2.939→49.256 Å / Num. obs: 15930 / % possible obs: 99.8 % / Redundancy: 4.5 % / CC1/2: 0.988 / Rmerge(I) obs: 0.141 / Rpim(I) all: 0.074 / Rrim(I) all: 0.16 / Net I/σ(I): 7.9
Reflection shellResolution: 2.939→3.04 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.63 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1551 / CC1/2: 0.686 / Rpim(I) all: 0.454 / Rrim(I) all: 0.782 / % possible all: 98.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
SAINTdata scaling
SAINTdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.939→49.256 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.875 / SU B: 32.419 / SU ML: 0.307 / Cross valid method: FREE R-VALUE / ESU R Free: 0.441
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2629 773 4.854 %
Rwork0.213 15151 -
all0.215 --
obs-15924 99.724 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 46.308 Å2
Baniso -1Baniso -2Baniso -3
1--0.44 Å2-0 Å2-0.914 Å2
2--2.168 Å2-0 Å2
3----0.976 Å2
Refinement stepCycle: LAST / Resolution: 2.939→49.256 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4539 0 151 60 4750
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0124786
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164590
X-RAY DIFFRACTIONr_angle_refined_deg0.9141.8556481
X-RAY DIFFRACTIONr_angle_other_deg0.3351.77810596
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.655567
X-RAY DIFFRACTIONr_dihedral_angle_2_deg12.4258.48843
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.43310864
X-RAY DIFFRACTIONr_dihedral_angle_6_deg12.95310204
X-RAY DIFFRACTIONr_chiral_restr0.0430.2714
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025470
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021024
X-RAY DIFFRACTIONr_nbd_refined0.1960.2950
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1750.24162
X-RAY DIFFRACTIONr_nbtor_refined0.1720.22259
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0730.22271
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1370.2120
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0750.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.10.28
X-RAY DIFFRACTIONr_nbd_other0.1450.271
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1660.27
X-RAY DIFFRACTIONr_mcbond_it1.0722.2382283
X-RAY DIFFRACTIONr_mcbond_other1.0722.2382283
X-RAY DIFFRACTIONr_mcangle_it1.8954.0122845
X-RAY DIFFRACTIONr_mcangle_other1.8954.0132846
X-RAY DIFFRACTIONr_scbond_it1.5712.6052503
X-RAY DIFFRACTIONr_scbond_other1.3332.4662452
X-RAY DIFFRACTIONr_scangle_it2.6094.7393628
X-RAY DIFFRACTIONr_scangle_other2.2654.4883551
X-RAY DIFFRACTIONr_lrange_it7.28721.4295195
X-RAY DIFFRACTIONr_lrange_other7.15521.4235187
X-RAY DIFFRACTIONr_ncsr_local_group_10.0870.058937
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.087040.05009
12AX-RAY DIFFRACTIONLocal ncs0.087040.05009
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.939-3.0150.353590.27711100.28111900.9280.95998.23530.277
3.015-3.0970.317550.2910420.29210970.9260.9521000.29
3.097-3.1870.356550.28310620.28711190.9290.95199.82130.283
3.187-3.2840.353500.25510290.2610790.9210.9581000.255
3.284-3.3920.246430.2279950.22810380.9690.9691000.227
3.392-3.510.252340.219650.21110010.9580.97599.80020.21
3.51-3.6420.207470.2129250.2129750.9680.97599.69230.212
3.642-3.790.262500.2069080.2099600.9580.97999.79170.206
3.79-3.9570.292420.2018310.2058740.9630.97799.88560.201
3.957-4.1490.241450.1898410.1928870.9630.97999.88730.189
4.149-4.3720.231580.1757670.1788250.9740.9821000.175
4.372-4.6350.228320.1797330.1817650.9690.9811000.179
4.635-4.9510.233410.1866780.1897190.9560.981000.186
4.951-5.3440.248400.1966560.1996960.9720.9811000.196
5.344-5.8470.266340.2136040.2166390.9730.97799.84350.213
5.847-6.5250.303320.2345400.2385720.9530.9731000.234
6.525-7.5130.224170.2364970.2365140.9730.9671000.236
7.513-9.1480.357190.1564180.1634370.9290.9851000.156
9.148-12.720.122100.1823410.183530.9920.98299.43340.182
12.72-49.2560.212100.3092080.3042190.9750.94399.54340.309
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)
16.10082.7435-0.93783.6701-1.26775.3267-0.0013-0.21160.71610.0931-0.257-0.378-0.49850.30890.25830.0519-0.0372-0.02890.19010.05220.3343-5.91013.153914.3643
24.782-1.0834-0.65331.53690.13084.60410.07580.15590.3276-0.0870.0555-0.0094-0.1901-0.1749-0.13130.0173-0.0162-0.00460.09860.06510.0657-31.18-4.551620.5319
33.20883.0344-0.93236.7593-2.09124.35090.0511-0.1428-0.3004-0.1429-0.0938-0.30870.18320.25390.04270.03030.04120.03490.18870.05860.1732-17.8852-23.1728-20.2765
46.0656-1.23520.66291.87390.0393.48060.2013-0.27910.0664-0.1086-0.2552-0.0723-0.1003-0.14860.05390.1011-0.0797-0.00470.2131-0.02820.0769-42.0704-28.5465-10.5546
Refinement TLS group
IDRefine-IDRefine TLS-IDSelectionAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1ALLA465 - 563
2X-RAY DIFFRACTION2ALLA564 - 764

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