PDB-8w2k: Crystal Structure of human Tryptophan 2,3-dioxygenase in complex ...

ID or keywords:

Entry

Database: PDB / ID: 8w2k

Title

Crystal Structure of human Tryptophan 2,3-dioxygenase in complex with PAN3F inhibitor

Components

Tryptophan 2,3-dioxygenase

Keywords

OXIDOREDUCTASE/INHIBITOR / Inhibitor / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex

Function / homology

Function and homology information

response to nitroglycerin / tryptophan catabolic process to acetyl-CoA / tryptophan 2,3-dioxygenase / tryptophan 2,3-dioxygenase activity / tryptophan catabolic process to kynurenine / Tryptophan catabolism / amino acid binding / oxygen binding / protein homotetramerization / heme binding ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.45 Å

Authors

Geeraerts, Z. / Yeh, S.-R.

Funding support

United States, 2items

Organization	Grant number	Country
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	GM115773	United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	GM151419	United States

Citation

Journal: J.Med.Chem. / Year: 2024
Title: Structural Insights into Protein-Inhibitor Interactions in Human Tryptophan Dioxygenase.
Authors: Geeraerts, Z. / Ishigami, I. / Lewis-Ballester, A. / Pham, K.N. / Kozlova, A. / Mathieu, C. / Frederick, R. / Yeh, S.R.

History

Deposition	Feb 20, 2024	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Aug 21, 2024	Provider: repository / Type: Initial release
Revision 1.1	Sep 4, 2024	Group: Database references / Category: citation Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2	Sep 11, 2024	Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	8w2k.cif.gz	724.3 KB	Display	PDBx/mmCIF format
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Validation report

Summary document	8w2k_validation.pdf.gz	2.9 MB	Display	wwPDB validaton report
Full document	8w2k_full_validation.pdf.gz	2.9 MB	Display
Data in XML	8w2k_validation.xml.gz	50 KB	Display
Data in CIF	8w2k_validation.cif.gz	66.4 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/w2/8w2k ftp://data.pdbj.org/pub/pdb/validation_reports/w2/8w2k	HTTPS FTP

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Related structure data

Related structure data	7lu7C 8vtqC 8vugC 8vzvC 8w1hC 9at2C 9b17C 9b1qC 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

Deposited unit

A: Tryptophan 2,3-dioxygenase

B: Tryptophan 2,3-dioxygenase

C: Tryptophan 2,3-dioxygenase

D: Tryptophan 2,3-dioxygenase

hetero molecules

186 kDa, 4 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author&software

Unit cell

Length a, b, c (Å)	144.081, 154.84, 88.757
Angle α, β, γ (deg.)	90, 90, 90
Int Tables number	18
Space group name H-M	P2₁2₁2

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
7	4	A
8	4	A
9	5	A
10	5	A
11	6	A
12	6	A

NCS domain segments:

Beg auth comp-ID: LEU / Beg label comp-ID: LEU / Auth asym-ID: A / Label asym-ID: A

Dom-ID	Component-ID	Ens-ID	End auth comp-ID	End label comp-ID	Auth seq-ID	Label seq-ID
1	1	1	HIS	HIS	40 - 391	24 - 375
2	1	1	HIS	HIS	40 - 391	24 - 375
3	2	2	LEU	LEU	40 - 389	24 - 373
4	2	2	LEU	LEU	40 - 389	24 - 373
5	3	3	PHE	PHE	40 - 388	24 - 372
6	3	3	PHE	PHE	40 - 388	24 - 372
7	4	4	LEU	LEU	40 - 389	24 - 373
8	4	4	LEU	LEU	40 - 389	24 - 373
9	5	5	LEU	LEU	40 - 389	24 - 373
10	5	5	LEU	LEU	40 - 389	24 - 373
11	6	6	LEU	LEU	40 - 389	24 - 373
12	6	6	LEU	LEU	40 - 389	24 - 373

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
4	Local NCS retraints between domains: 7 8
5	Local NCS retraints between domains: 9 10
6	Local NCS retraints between domains: 11 12

#1: Protein	Tryptophan 2,3-dioxygenase / TDO / Tryptamin 2 / 3-dioxygenase / Tryptophan oxygenase / TRPO / Tryptophan pyrrolase / Tryptophanase Mass: 45182.535 Da / Num. of mol.: 4 / Fragment: UNP residues 18-389 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TDO2, TDO / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P48775, tryptophan 2,3-dioxygenase
#2: Chemical	ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₃₄H₃₂FeN₄O₄
#3: Chemical	ChemComp-ZIQ / alpha-methyl-L-tryptophan Type: L-peptide linking / Mass: 218.252 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₁₂H₁₄N₂O₂
#4: Chemical	ChemComp-A1AE7 / (6M)-6-(6-fluoro-1H-indol-3-yl)-1-[2-(piperazin-1-yl)ethyl]-1H-benzotriazole Mass: 364.419 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₂₀H₂₁FN₆ / Feature type: SUBJECT OF INVESTIGATION
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 12 / 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: 2.74 Å³/Da / Density % sol: 55.09 %
Crystal grow	Temperature: 298 K / Method: microbatch Details: 50 mM Sodium Citrate pH 5.6, 2.0% Tacsimate pH 5.0, 5.0% PEG 3350

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Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

APS

/ Beamline: 31-ID / Wavelength: 0.9793 Å

Detector

Type: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 9, 2023

Radiation

Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray

Radiation wavelength

Wavelength: 0.9793 Å / Relative weight: 1

Reflection

Resolution: 2.45→154.84 Å / Num. obs: 73492 / % possible obs: 99.8 % / Redundancy: 6.1 % / CC_1/2: 0.999 / R_merge(I) obs: 0.067 / R_pim(I) all: 0.043 / R_rim(I) all: 0.08 / Net I/σ(I): 12.6

Reflection shell

Diffraction-ID: 1

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Num. unique obs	CC_1/2	R_pim(I) all	R_rim(I) all
12-154.84	5.7	0.029	726	0.998	0.018	0.035
2.45-2.5	5.3	1.33	4443	0.484	0.887	1.607

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Processing

Software

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

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 2.45→77.54 Å / Cor.coef. F_o:F_c: 0.96 / Cor.coef. F_o:F_c free: 0.944 / WR_factor R_free: 0.249 / WR_factor R_work: 0.199 / SU B: 25.673 / SU ML: 0.245 / Average fsc free: 0.9449 / Average fsc work: 0.9595 / Cross valid method: FREE R-VALUE / ESU R: 0.371 / ESU R Free: 0.253
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2442	3662	4.987 %
R_work	0.1994	69765	-
all	0.202	-	-
obs	-	73427	99.686 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 91.048 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.078 Å²	-0 Å²	-0 Å²
2-	-	-3.826 Å²	0 Å²
3-	-	-	3.905 Å²

Refinement step

Cycle: LAST / Resolution: 2.45→77.54 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	11675	0	344	12	12031

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.008	0.012	12343
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.016	11654
X-RAY DIFFRACTION	r_angle_refined_deg	1.556	1.889	16680
X-RAY DIFFRACTION	r_angle_other_deg	0.543	1.791	26721
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	4.847	5	1364
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	13.836	6.111	108
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	13.805	10	2271
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	13.141	10	651
X-RAY DIFFRACTION	r_chiral_restr	0.076	0.2	1710
X-RAY DIFFRACTION	r_gen_planes_refined	0.008	0.02	14484
X-RAY DIFFRACTION	r_gen_planes_other	0.004	0.02	3128
X-RAY DIFFRACTION	r_nbd_refined	0.239	0.2	2658
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.185	0.2	10386
X-RAY DIFFRACTION	r_nbtor_refined	0.189	0.2	6065
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.071	0.2	6388
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.142	0.2	273
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.075	0.2	2
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.339	0.2	14
X-RAY DIFFRACTION	r_nbd_other	0.216	0.2	30
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.209	0.2	6
X-RAY DIFFRACTION	r_mcbond_it	5.605	5.295	5494
X-RAY DIFFRACTION	r_mcbond_other	5.588	5.295	5492
X-RAY DIFFRACTION	r_mcangle_it	8.18	9.514	6844
X-RAY DIFFRACTION	r_mcangle_other	8.177	9.515	6844
X-RAY DIFFRACTION	r_scbond_it	6.245	5.863	6849
X-RAY DIFFRACTION	r_scbond_other	6.245	5.863	6850
X-RAY DIFFRACTION	r_scangle_it	9.349	10.57	9836
X-RAY DIFFRACTION	r_scangle_other	9.349	10.571	9837
X-RAY DIFFRACTION	r_lrange_it	14.482	65.077	51280
X-RAY DIFFRACTION	r_lrange_other	14.482	65.077	51276
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.114	0.05	11542
X-RAY DIFFRACTION	r_ncsr_local_group_2	0.118	0.05	11326
X-RAY DIFFRACTION	r_ncsr_local_group_3	0.121	0.05	11351
X-RAY DIFFRACTION	r_ncsr_local_group_4	0.118	0.05	11367
X-RAY DIFFRACTION	r_ncsr_local_group_5	0.121	0.05	11410
X-RAY DIFFRACTION	r_ncsr_local_group_6	0.122	0.05	11349

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	0.11376	0.05008
1	2	A	X-RAY DIFFRACTION	Local ncs	0.11376	0.05008
2	3	A	X-RAY DIFFRACTION	Local ncs	0.1181	0.05008
2	4	A	X-RAY DIFFRACTION	Local ncs	0.1181	0.05008
3	5	A	X-RAY DIFFRACTION	Local ncs	0.12081	0.05008
3	6	A	X-RAY DIFFRACTION	Local ncs	0.12081	0.05008
4	7	A	X-RAY DIFFRACTION	Local ncs	0.1184	0.05008
4	8	A	X-RAY DIFFRACTION	Local ncs	0.1184	0.05008
5	9	A	X-RAY DIFFRACTION	Local ncs	0.12079	0.05008
5	10	A	X-RAY DIFFRACTION	Local ncs	0.12079	0.05008
6	11	A	X-RAY DIFFRACTION	Local ncs	0.12223	0.05008
6	12	A	X-RAY DIFFRACTION	Local ncs	0.12223	0.05008

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
2.45-2.514	0.381	286	0.351	5055	0.352	5370	0.877	0.898	99.46	0.342
2.514-2.582	0.345	275	0.322	4938	0.323	5233	0.907	0.917	99.6178	0.31
2.582-2.657	0.329	218	0.306	4864	0.307	5097	0.919	0.934	99.7057	0.292
2.657-2.739	0.332	237	0.287	4692	0.289	4942	0.932	0.947	99.7369	0.268
2.739-2.829	0.303	250	0.258	4580	0.26	4845	0.941	0.958	99.6904	0.236
2.829-2.928	0.29	233	0.241	4386	0.243	4630	0.942	0.965	99.7624	0.216
2.928-3.038	0.265	222	0.222	4258	0.224	4492	0.955	0.97	99.7329	0.199
3.038-3.162	0.273	213	0.215	4119	0.218	4340	0.952	0.97	99.8157	0.195
3.162-3.302	0.248	215	0.211	3958	0.213	4179	0.956	0.972	99.8564	0.192
3.302-3.463	0.254	172	0.205	3817	0.207	3991	0.955	0.973	99.9499	0.19
3.463-3.65	0.242	183	0.202	3600	0.204	3785	0.966	0.976	99.9472	0.193
3.65-3.871	0.253	184	0.2	3423	0.203	3615	0.963	0.976	99.7787	0.196
3.871-4.137	0.216	174	0.186	3193	0.188	3394	0.974	0.979	99.2045	0.189
4.137-4.468	0.207	147	0.16	3032	0.162	3184	0.976	0.985	99.843	0.167
4.468-4.893	0.184	139	0.146	2760	0.148	2906	0.978	0.987	99.7591	0.157
4.893-5.468	0.244	150	0.165	2526	0.17	2685	0.967	0.984	99.6648	0.179
5.468-6.308	0.26	138	0.199	2217	0.202	2372	0.965	0.977	99.2833	0.211
6.308-7.713	0.253	104	0.207	1914	0.21	2025	0.959	0.973	99.6543	0.23
7.713-10.854	0.199	84	0.158	1515	0.161	1602	0.979	0.984	99.8127	0.191
10.854-77.54	0.247	38	0.219	918	0.22	969	0.957	0.959	98.6584	0.258

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	1.3973	1.2346	-0.4426	3.3403	-0.3764	0.8043	0.0154	-0.0376	-0.087	0.3523	-0.0262	-0.4224	-0.1025	0.2292	0.0108	0.0666	-0.02	-0.0495	0.283	-0.0077	0.1537	39.6365	-40.1562	-43.3647
2	3.0318	0.3343	-1.699	0.7822	-0.2963	1.4959	-0.1924	0.2366	-0.4516	-0.0664	0.0411	0.2329	0.0815	-0.4069	0.1514	0.078	0.0124	-0.0456	0.2586	0.0076	0.2916	5.5296	-60.5751	-33.4892
3	1.5676	-0.2655	0.4235	2.4625	-1.718	2.4711	-0.0047	-0.4564	0.0316	0.5397	-0.3052	-0.9567	-0.1226	0.5935	0.3099	0.2787	-0.0413	-0.2456	0.6552	0.0131	0.483	28.7972	-44.772	-15.4989
4	1.5868	0.1085	-0.2729	1.5299	-0.2877	3.1883	-0.0268	0.3821	0.1369	-0.1606	0.0327	0.2991	0.1389	-0.377	-0.0059	0.0239	-0.0125	-0.0435	0.3399	0.0492	0.1321	7.1878	-34.6187	-48.6085

Refinement TLS group

Selection: ALL

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