PDB-9cd7: FGFR3 Kinase Domain with Inhibitor TYRA-300

ID or keywords:

Entry

Database: PDB / ID: 9cd7

Title

FGFR3 Kinase Domain with Inhibitor TYRA-300

Components

Fibroblast growth factor receptor 3

Keywords

TRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Transferase / Inhibitor / Cancer / Achondroplasia / FGFR3 / FGFR / 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 / endochondral bone growth / chondrocyte proliferation / FGFR3b ligand binding and activation / fibroblast growth factor receptor activity / Signaling by activated point mutants of FGFR3 ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.53 Å

Authors

Hoffman, I.H. / Nelson, K.J. / Rideout, M.C. / Nix, J.C. / Frye, C. / Bensen, D.C. / Hudkins, R.L.

Funding support

United States, 1items

Citation

Journal: 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

Deposition	Jun 24, 2024	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Sep 25, 2024	Provider: repository / Type: Initial release
Revision 1.1	Oct 2, 2024	Group: Database references / Category: citation Item: _citation.journal_volume / _citation.page_first / _citation.page_last

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	9cd7.cif.gz	454.4 KB	Display	PDBx/mmCIF format
PDB format	pdb9cd7.ent.gz		Display	PDB format
PDBx/mmJSON format	9cd7.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	9cd7_validation.pdf.gz	1.1 MB	Display	wwPDB validaton report
Full document	9cd7_full_validation.pdf.gz	1.1 MB	Display
Data in XML	9cd7_validation.xml.gz	36.8 KB	Display
Data in CIF	9cd7_validation.cif.gz	47.2 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/cd/9cd7 ftp://data.pdbj.org/pub/pdb/validation_reports/cd/9cd7	HTTPS FTP

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Related structure data

Related structure data	9cd5C C: citing same article (ref.)
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#234 - Jun 2019 MDM2 and Cancer similarity (1) #148 - Apr 2012 Ras Protein similarity (3) #267 - Mar 2022 Vascular Endothelial Growth Factor (VegF similarity (3) #185 - May 2015 Titin similarity (2) #247 - Jul 2020 Myelin-associated Glycoprotein similarity (1) #195 - Mar 2016 RAF Protein Kinases similarity (3)

Deposited unit

A: Fibroblast growth factor receptor 3

B: Fibroblast growth factor receptor 3

C: Fibroblast growth factor receptor 3

hetero molecules

109 kDa, 3 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Fibroblast growth factor receptor 3

hetero molecules

defined by author
Evidence: gel filtration
36 kDa, 1 polymers

2

B: Fibroblast growth factor receptor 3

hetero molecules

defined by author
36.4 kDa, 1 polymers

3

C: Fibroblast growth factor receptor 3

hetero molecules

defined by author
36.4 kDa, 1 polymers

Unit cell

Length a, b, c (Å)	180.686, 55.588, 138.668
Angle α, β, γ (deg.)	90.000, 127.452, 90.000
Int Tables number	5
Space group name H-M	C121

Noncrystallographic symmetry (NCS)

NCS domain:

ID	Ens-ID	Details
1	1	A
2	1	A
3	2	A
4	2	A
5	3	A
6	3	A

NCS domain segments:

Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: THR / End label comp-ID: THR / Auth asym-ID: A / Label asym-ID: A / Auth seq-ID: 458 - 755 / Label seq-ID: 11 - 308

Dom-ID	Component-ID	Ens-ID
1	1	1
2	1	1
3	2	2
4	2	2
5	3	3
6	3	3

NCS ensembles :

ID	Details
1	Local NCS retraints between domains: 1 2
2	Local NCS retraints between domains: 3 4
3	Local NCS retraints between domains: 5 6

#1: Protein	Fibroblast growth factor receptor 3 / FGFR-3 Mass: 35107.359 Da / Num. of mol.: 3 / Mutation: C482A, C582S, K650E Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR3, JTK4 / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: P22607, receptor protein-tyrosine kinase
#2: 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.: 3 / Source method: obtained synthetically / Formula: C₂₅H₂₄Cl₂N₆O₃S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL Mass: 92.094 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C₃H₈O₃
#4: Chemical	ChemComp-SO4 / SULFATE ION Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO₄
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 130 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.62 Å³/Da / Density % sol: 53.13 %
Crystal grow	Temperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5.25 Details: 17% PEG Smear Medium 10% Tacsimate pH 5.25 0.2M Ammonium Sulfate

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
Detector	Type: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: May 16, 2024
Radiation	Monochromator: Double-crystal Si(111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1 Å / Relative weight: 1
Reflection	Resolution: 2.53→48.17 Å / Num. obs: 36870 / % possible obs: 99.8 % / Redundancy: 6.8 % / CC_1/2: 0.966 / R_merge(I) obs: 0.443 / R_pim(I) all: 0.183 / R_rim(I) all: 0.48 / Χ²: 1.06 / Net I/σ(I): 4.7 / Num. measured all: 249415
Reflection shell	Resolution: 2.53→2.64 Å / % possible obs: 100 % / Redundancy: 7 % / R_merge(I) obs: 3.534 / Num. measured all: 31050 / Num. unique obs: 4446 / CC_1/2: 0.21 / R_pim(I) all: 1.428 / R_rim(I) all: 3.817 / Χ²: 1.03 / Net I/σ(I) obs: 0.6

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0425	refinement
Aimless		data scaling
XDS		data reduction
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 2.53→40.003 Å / Cor.coef. F_o:F_c: 0.928 / Cor.coef. F_o:F_c free: 0.903 / SU B: 36.322 / SU ML: 0.341 / Cross valid method: FREE R-VALUE / ESU R: 0.566 / ESU R Free: 0.305
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2671	1654	4.487 %
R_work	0.2287	35207	-
all	0.23	-	-
obs	-	36861	99.765 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL PLUS MASK

Displacement parameters

B_iso mean: 54.443 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.865 Å²	-0 Å²	-1.008 Å²
2-	-	1.966 Å²	0 Å²
3-	-	-	0.203 Å²

Refinement step

Cycle: LAST / Resolution: 2.53→40.003 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	6577	0	227	130	6934

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.003	0.012	6937
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.016	6732
X-RAY DIFFRACTION	r_angle_refined_deg	1.037	1.85	9377
X-RAY DIFFRACTION	r_angle_other_deg	0.381	1.769	15513
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.16	5	823
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	11.196	8.629	62
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	13.024	10	1210
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	11.556	10	289
X-RAY DIFFRACTION	r_chiral_restr	0.052	0.2	1045
X-RAY DIFFRACTION	r_gen_planes_refined	0.003	0.02	7908
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	1495
X-RAY DIFFRACTION	r_nbd_refined	0.2	0.2	1337
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.181	0.2	6073
X-RAY DIFFRACTION	r_nbtor_refined	0.175	0.2	3317
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.074	0.2	3324
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.143	0.2	177
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.205	0.2	42
X-RAY DIFFRACTION	r_nbd_other	0.19	0.2	105
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.301	0.2	8
X-RAY DIFFRACTION	r_mcbond_it	3.813	4.132	3319
X-RAY DIFFRACTION	r_mcbond_other	3.803	4.133	3319
X-RAY DIFFRACTION	r_mcangle_it	6.062	7.411	4133
X-RAY DIFFRACTION	r_mcangle_other	6.064	7.413	4134
X-RAY DIFFRACTION	r_scbond_it	4.321	4.609	3618
X-RAY DIFFRACTION	r_scbond_other	4.085	4.584	3603
X-RAY DIFFRACTION	r_scangle_it	6.789	8.29	5232
X-RAY DIFFRACTION	r_scangle_other	6.59	8.249	5209
X-RAY DIFFRACTION	r_lrange_it	9.416	40.936	7521
X-RAY DIFFRACTION	r_lrange_other	9.418	40.942	7517
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.073	0.05	8592
X-RAY DIFFRACTION	r_ncsr_local_group_2	0.083	0.05	8553
X-RAY DIFFRACTION	r_ncsr_local_group_3	0.077	0.05	8971

Refine LS restraints NCS

Ens-ID	Dom-ID	Auth asym-ID	Refine-ID	Type	Rms dev position (Å)	Weight position
1	1	A	X-RAY DIFFRACTION	Local ncs	0.07272	0.0501
1	2	A	X-RAY DIFFRACTION	Local ncs	0.07272	0.0501
2	3	A	X-RAY DIFFRACTION	Local ncs	0.0828	0.0501
2	4	A	X-RAY DIFFRACTION	Local ncs	0.0828	0.0501
3	5	A	X-RAY DIFFRACTION	Local ncs	0.07719	0.0501
3	6	A	X-RAY DIFFRACTION	Local ncs	0.07719	0.0501

LS refinement shell

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

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	R_factor all	Num. reflection all	Fsc free	Fsc work	% reflection obs (%)	WR_factor R_work
2.53-2.595	0.409	135	0.372	2506	0.374	2641	0.861	0.882	100	0.369
2.595-2.666	0.394	102	0.354	2556	0.356	2660	0.884	0.902	99.9248	0.347
2.666-2.743	0.334	125	0.344	2420	0.343	2549	0.91	0.904	99.8431	0.336
2.743-2.827	0.388	126	0.327	2368	0.33	2501	0.887	0.921	99.7201	0.315
2.827-2.919	0.404	89	0.316	2327	0.319	2421	0.891	0.927	99.7935	0.302
2.919-3.021	0.339	86	0.293	2234	0.294	2324	0.928	0.938	99.8279	0.271
3.021-3.135	0.337	95	0.274	2148	0.277	2252	0.927	0.948	99.6004	0.248
3.135-3.262	0.297	119	0.259	2075	0.261	2205	0.942	0.955	99.5011	0.231
3.262-3.406	0.284	88	0.235	1972	0.237	2062	0.946	0.966	99.903	0.209
3.406-3.571	0.259	86	0.222	1895	0.224	1985	0.955	0.97	99.7985	0.196
3.571-3.762	0.237	80	0.204	1841	0.205	1924	0.961	0.979	99.8441	0.18
3.762-3.988	0.204	84	0.171	1718	0.172	1804	0.973	0.984	99.8891	0.149
3.988-4.261	0.196	84	0.166	1617	0.168	1702	0.976	0.983	99.9412	0.146
4.261-4.598	0.214	69	0.153	1529	0.155	1602	0.972	0.985	99.7503	0.132
4.598-5.03	0.233	74	0.168	1390	0.171	1464	0.967	0.983	100	0.142
5.03-5.613	0.245	62	0.181	1265	0.184	1330	0.968	0.982	99.7744	0.154
5.613-6.46	0.188	43	0.189	1126	0.189	1179	0.981	0.98	99.1518	0.16
6.46-7.86	0.209	38	0.177	987	0.178	1025	0.973	0.98	100	0.154
7.86-10.908	0.201	41	0.156	759	0.159	800	0.979	0.987	100	0.15
10.908-40.003	0.234	28	0.295	474	0.291	503	0.971	0.949	99.8012	0.293

Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

ID	L11 (°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	0.5711	-0.3443	-0.3703	1.4318	0.6933	0.9012	-0.0229	-0.0456	0.0097	0.1108	-0.0026	0.013	0.039	-0.0859	0.0255	0.0504	-0.0067	-0.026	0.1537	0.0185	0.0215	16.6664	-7.6938	9.0432
2	0.7496	0.0904	0.0088	0.3728	-0.8678	2.1072	-0.0146	0.0215	-0.0066	-0.0565	-0.006	-0.0067	0.1362	-0.0187	0.0206	0.0705	-0.0046	-0.0293	0.0654	-0.0147	0.0196	43.12	6.7312	27.6836
3	0.47	-0.2581	0.1097	0.2387	0.1145	2.1632	-0.0237	-0.0747	-0.092	0.0318	0.0086	-0.0399	0.194	0.1107	0.0151	0.126	0.0294	-0.0094	0.1551	0.023	0.1387	74.5446	-6.4984	38.8303

Refinement TLS group

Selection: ALL

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