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- PDB-8w38: TAS-120 covalent structure with FGFR2 molecular brake mutant -

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Basic information

Entry
Database: PDB / ID: 8w38
TitleTAS-120 covalent structure with FGFR2 molecular brake mutant
ComponentsFibroblast growth factor receptor 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / FGFR2 / TAS-120 / inhibitor / complex / transferase / transferase inhibitor complex / kinase / molecular brake / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung 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 / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland development / prostate gland morphogenesis / otic vesicle formation / 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 / embryonic organ morphogenesis / branching morphogenesis of a nerve / endochondral bone growth / morphogenesis of embryonic epithelium / bud elongation involved in lung branching / epidermis morphogenesis / positive regulation of epithelial cell proliferation involved in lung morphogenesis / reproductive structure development / limb bud formation / membranous septum morphogenesis / gland morphogenesis / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / embryonic digestive tract morphogenesis / mesenchymal cell differentiation / positive regulation of phospholipase activity / epithelial cell proliferation involved in salivary gland morphogenesis / mesenchymal cell proliferation involved in lung development / branching involved in prostate gland morphogenesis / FGFR2b ligand binding and activation / branching involved in labyrinthine layer morphogenesis / lung lobe 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 pattern specification / pyramidal neuron development / lung-associated mesenchyme development / embryonic cranial skeleton morphogenesis / outflow tract septum morphogenesis / regulation of smoothened signaling pathway / mesodermal cell differentiation / bone morphogenesis / digestive tract development / odontogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / skeletal system morphogenesis / organ growth / inner ear morphogenesis / hair follicle morphogenesis / Signaling by FGFR2 IIIa TM / lung alveolus development / ventricular cardiac muscle tissue morphogenesis / regulation of osteoblast differentiation / PI-3K cascade:FGFR2 / prostate epithelial cord elongation / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / bone mineralization / midbrain development / fibroblast growth factor binding / positive regulation of cell division / PI3K Cascade / excitatory synapse / epithelial to mesenchymal transition / cell fate commitment / fibroblast growth factor receptor signaling pathway / positive regulation of Wnt signaling pathway / negative regulation of keratinocyte proliferation / embryonic organ development / cellular response to transforming growth factor beta stimulus / regulation of ERK1 and ERK2 cascade / SHC-mediated cascade:FGFR2 / positive regulation of cardiac muscle cell proliferation / positive regulation of vascular associated smooth muscle cell proliferation / FRS-mediated FGFR2 signaling / positive regulation of cell cycle / cellular response to retinoic acid / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / lung development / Negative regulation of FGFR2 signaling / peptidyl-tyrosine phosphorylation / animal organ morphogenesis / positive regulation of epithelial cell proliferation / post-embryonic development / receptor protein-tyrosine kinase / bone development / Constitutive Signaling by Aberrant PI3K in Cancer
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 / 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
Chem-TZ0 / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsHoffman, I.D. / Nelson, K.J. / Bensen, D.C. / Bailey, J.B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Ann Oncol / Year: 2025
Title: A model for decoding resistance in precision oncology: acquired resistance to FGFR inhibitors in cholangiocarcinoma.
Authors: Goyal, L. / DiToro, D. / Facchinetti, F. / Martin, E.E. / Peng, P. / Baiev, I. / Iyer, R. / Maurer, J. / Reyes, S. / Zhang, K. / Majeed, U. / Berchuck, J.E. / Chen, C.T. / Walmsley, C. / ...Authors: Goyal, L. / DiToro, D. / Facchinetti, F. / Martin, E.E. / Peng, P. / Baiev, I. / Iyer, R. / Maurer, J. / Reyes, S. / Zhang, K. / Majeed, U. / Berchuck, J.E. / Chen, C.T. / Walmsley, C. / Pinto, C. / Vasseur, D. / Gordan, J.D. / Mody, K. / Borad, M. / Karasic, T. / Damjanov, N. / Danysh, B.P. / Wehrenberg-Klee, E. / Kambadakone, A.R. / Saha, S.K. / Hoffman, I.D. / Nelson, K.J. / Iyer, S. / Qiang, X. / Sun, C. / Wang, H. / Li, L. / Javle, M. / Lin, B. / Harris, W. / Zhu, A.X. / Cleary, J.M. / Flaherty, K.T. / Harris, T. / Shroff, R.T. / Leshchiner, I. / Parida, L. / Kelley, R.K. / Fan, J. / Stone, J.R. / Uboha, N.V. / Hirai, H. / Sootome, H. / Wu, F. / Bensen, D.C. / Hollebecque, A. / Friboulet, L. / Lennerz, J.K. / Getz, G. / Juric, D.
History
DepositionFeb 22, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year

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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
C: Fibroblast growth factor receptor 2
D: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,85715
Polymers148,5114
Non-polymers2,34611
Water1,04558
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,6423
Polymers37,1281
Non-polymers5152
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8345
Polymers37,1281
Non-polymers7074
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8345
Polymers37,1281
Non-polymers7074
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5462
Polymers37,1281
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)80.252, 129.872, 131.423
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: THR / End label comp-ID: THR / Refine code: _ / Auth seq-ID: 467 - 764 / Label seq-ID: 23 - 320

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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


Mass: 37127.676 Da / Num. of mol.: 4 / Mutation: N549D, D650V
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-TZ0 / 1-[(3S)-3-{4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}pyrrolidin-1-yl]prop-2-en-1-one


Mass: 418.448 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H22N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 58 / 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: 2.31 Å3/Da / Density % sol: 46.66 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 25% PEG 3350, 0.2M LiSO4, 0.1M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 8, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→47.34 Å / Num. obs: 42997 / % possible obs: 100 % / Redundancy: 8.9 % / CC1/2: 0.993 / Rmerge(I) obs: 0.312 / Rpim(I) all: 0.11 / Rrim(I) all: 0.331 / Net I/σ(I): 5.8
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 9.1 % / Rmerge(I) obs: 1.573 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 4244 / CC1/2: 0.64 / Rpim(I) all: 0.549 / Rrim(I) all: 1.668 / % possible all: 100

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Processing

Software
NameVersionClassification
SADABSV8.40Bdata scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
SAINTdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→35 Å / Cor.coef. Fo:Fc: 0.857 / Cor.coef. Fo:Fc free: 0.841 / SU B: 48.981 / SU ML: 0.461 / SU R Cruickshank DPI: 1.4887 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.489 / ESU R Free: 0.454 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : WITH TLS ADDED. The authors state that this data set has translational NCS (2 mol), pseudo-P212121-symmetry, and two out of the ...Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : WITH TLS ADDED. The authors state that this data set has translational NCS (2 mol), pseudo-P212121-symmetry, and two out of the four molecules in the asymmetric unit have large regions of electron density that are not resolvable in a discrete position, resulting in poor statistics.
RfactorNum. reflection% reflectionSelection details
Rfree0.3587 1998 4.7 %RANDOM
Rwork0.3359 ---
obs0.337 40873 99.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 217.37 Å2 / Biso mean: 62.248 Å2 / Biso min: 34.49 Å2
Baniso -1Baniso -2Baniso -3
1--1.72 Å20 Å20 Å2
2--5.63 Å2-0 Å2
3----3.91 Å2
Refinement stepCycle: final / Resolution: 2.6→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9163 0 159 58 9380
Biso mean--78.82 44.39 -
Num. residues----1146
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0129527
X-RAY DIFFRACTIONr_angle_refined_deg0.9181.66412874
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.54551138
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.82422.261482
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.357151731
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8361564
X-RAY DIFFRACTIONr_chiral_restr0.0680.21184
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.027096
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A95980.05
12B95980.05
21A91630.09
22C91630.09
31A87410.09
32D87410.09
41B89890.1
42C89890.1
51B87350.09
52D87350.09
61C89740.05
62D89740.05
LS refinement shellResolution: 2.6→2.667 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.383 143 -
Rwork0.376 2961 -
all-3104 -
obs--99.65 %
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)
11.9656-0.3222-0.41192.4141-0.09632.3362-0.0443-0.0451-0.1479-0.0876-0.0231-0.08820.2210.05030.06740.540.0511-0.03420.00670.02230.7226-60.39528.63451.667
21.7130.45890.17342.32450.16482.313-0.01450.0240.1605-0.0788-0.055-0.1169-0.21330.08980.06951.0633-0.0175-0.0070.26290.05920.9637-16.80436.06113.929
31.2049-0.2272-0.30293.4754-0.24661.8838-0.02870.03390.06370.03040.00850.0072-0.1571-0.15180.02020.49130.0067-0.05360.20440.03150.6355-18.88149.949.531
41.16460.10320.11962.9632-0.26921.5273-0.0274-0.0130.0166-0.020.00130.04310.1918-0.18640.02611.1128-0.00460.03390.37750.02580.9462-56.88114.74516.31
52.2432-1.39520.60120.9379-0.41060.2301-0.1045-0.4604-0.9324-0.03710.21690.2552-0.03120.154-0.11241.8421-0.28730.46841.33890.36421.919-27.31734.35837.234
60.0763-0.103-0.00390.29860.04750.0517-0.0549-0.0346-0.1185-0.08690.0018-0.0547-0.0951-0.04140.05320.63960.05610.00360.06720.0350.8162-40.55133.4246.257
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A467 - 566
2X-RAY DIFFRACTION1A567 - 764
3X-RAY DIFFRACTION1A801
4X-RAY DIFFRACTION2B467 - 566
5X-RAY DIFFRACTION2B567 - 764
6X-RAY DIFFRACTION2B801
7X-RAY DIFFRACTION3C465 - 566
8X-RAY DIFFRACTION3C567 - 764
9X-RAY DIFFRACTION3C801
10X-RAY DIFFRACTION4D467 - 566
11X-RAY DIFFRACTION4D567 - 764
12X-RAY DIFFRACTION4D800
13X-RAY DIFFRACTION5A802
14X-RAY DIFFRACTION5B802 - 804
15X-RAY DIFFRACTION5C802 - 804
16X-RAY DIFFRACTION6A901 - 926
17X-RAY DIFFRACTION6B901 - 907
18X-RAY DIFFRACTION6C901 - 923
19X-RAY DIFFRACTION6D901 - 902

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