PDB-9at2: Crystal Structure of human Tryptophan 2,3-dioxygenase in complex ...

ID or keywords:

Entry

Database: PDB / ID: 9at2

Title

Crystal Structure of human Tryptophan 2,3-dioxygenase in complex with PAN3 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: 2.25 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 26, 2024	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Aug 28, 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	9at2.cif.gz	723.1 KB	Display	PDBx/mmCIF format
PDB format	pdb9at2.ent.gz		Display	PDB format
PDBx/mmJSON format	9at2.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	9at2_validation.pdf.gz	3 MB	Display	wwPDB validaton report
Full document	9at2_full_validation.pdf.gz	3.1 MB	Display
Data in XML	9at2_validation.xml.gz	50.4 KB	Display
Data in CIF	9at2_validation.cif.gz	66.7 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/at/9at2 ftp://data.pdbj.org/pub/pdb/validation_reports/at/9at2	HTTPS FTP

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Related structure data

Related structure data	7lu7C 8vtqC 8vugC 8vzvC 8w1hC 8w2kC 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

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

1

Idetical with deposited unit
defined by author&software
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	144.042, 155.112, 88.515
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-A1AF5 / (6M)-6-(1H-indol-3-yl)-1-[2-(piperazin-1-yl)ethyl]-1H-1,2,3-benzotriazole Mass: 346.429 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₂₀H₂₂N₆ / Feature type: SUBJECT OF INVESTIGATION
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 23 / 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: 55.04 %
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: 2.25→155.11 Å / Num. obs: 94512 / % possible obs: 99.9 % / Redundancy: 6.5 % / CC_1/2: 0.999 / R_merge(I) obs: 0.058 / R_pim(I) all: 0.037 / R_rim(I) all: 0.069 / Net I/σ(I): 12.7

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
12.32-155.11	5.7	0.038	664	0.997	0.023	0.045
2.25-2.29	6.2	1.451	4618	0.47	0.946	1.741

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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: 2.25→88.672 Å / Cor.coef. F_o:F_c: 0.963 / Cor.coef. F_o:F_c free: 0.957 / WR_factor R_free: 0.231 / WR_factor R_work: 0.208 / SU B: 17.848 / SU ML: 0.186 / Average fsc free: 0.9553 / Average fsc work: 0.9634 / Cross valid method: FREE R-VALUE / ESU R: 0.248 / ESU R Free: 0.187
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2233	4874	5.16 %
R_work	0.2015	89576	-
all	0.203	-	-
obs	-	94450	99.781 %

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: 88.555 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-1.138 Å²	-0 Å²	0 Å²
2-	-	0.045 Å²	0 Å²
3-	-	-	1.093 Å²

Refinement step

Cycle: LAST / Resolution: 2.25→88.672 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	11644	0	340	23	12007

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.008	0.012	12309
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.016	11634
X-RAY DIFFRACTION	r_angle_refined_deg	1.529	1.889	16633
X-RAY DIFFRACTION	r_angle_other_deg	0.537	1.791	26671
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	4.636	5	1361
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	15.353	6.111	108
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	13.941	10	2265
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	13.932	10	649
X-RAY DIFFRACTION	r_chiral_restr	0.072	0.2	1705
X-RAY DIFFRACTION	r_gen_planes_refined	0.008	0.02	14451
X-RAY DIFFRACTION	r_gen_planes_other	0.004	0.02	3129
X-RAY DIFFRACTION	r_nbd_refined	0.234	0.2	2537
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.183	0.2	10115
X-RAY DIFFRACTION	r_nbtor_refined	0.187	0.2	5999
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.07	0.2	6282
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.146	0.2	220
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.07	0.2	1
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.263	0.2	10
X-RAY DIFFRACTION	r_nbd_other	0.254	0.2	35
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.276	0.2	6
X-RAY DIFFRACTION	r_mcbond_it	4.997	5.16	5479
X-RAY DIFFRACTION	r_mcbond_other	4.992	5.16	5477
X-RAY DIFFRACTION	r_mcangle_it	7.217	9.276	6827
X-RAY DIFFRACTION	r_mcangle_other	7.216	9.277	6827
X-RAY DIFFRACTION	r_scbond_it	6.051	5.774	6830
X-RAY DIFFRACTION	r_scbond_other	6.051	5.774	6831
X-RAY DIFFRACTION	r_scangle_it	8.937	10.367	9806
X-RAY DIFFRACTION	r_scangle_other	8.937	10.367	9807
X-RAY DIFFRACTION	r_lrange_it	13.025	63.385	50756
X-RAY DIFFRACTION	r_lrange_other	13.025	63.383	50748
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.112	0.05	11562
X-RAY DIFFRACTION	r_ncsr_local_group_2	0.12	0.05	11187
X-RAY DIFFRACTION	r_ncsr_local_group_3	0.11	0.05	11320
X-RAY DIFFRACTION	r_ncsr_local_group_4	0.116	0.05	11216
X-RAY DIFFRACTION	r_ncsr_local_group_5	0.116	0.05	11421
X-RAY DIFFRACTION	r_ncsr_local_group_6	0.126	0.05	11118

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	0.11151	0.05008
1	2	A	X-RAY DIFFRACTION	Local ncs	0.11151	0.05008
2	3	A	X-RAY DIFFRACTION	Local ncs	0.12028	0.05008
2	4	A	X-RAY DIFFRACTION	Local ncs	0.12028	0.05008
3	5	A	X-RAY DIFFRACTION	Local ncs	0.11022	0.05008
3	6	A	X-RAY DIFFRACTION	Local ncs	0.11022	0.05008
4	7	A	X-RAY DIFFRACTION	Local ncs	0.11583	0.05008
4	8	A	X-RAY DIFFRACTION	Local ncs	0.11583	0.05008
5	9	A	X-RAY DIFFRACTION	Local ncs	0.11624	0.05008
5	10	A	X-RAY DIFFRACTION	Local ncs	0.11624	0.05008
6	11	A	X-RAY DIFFRACTION	Local ncs	0.12555	0.05008
6	12	A	X-RAY DIFFRACTION	Local ncs	0.12555	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
2.25-2.308	0.338	348	0.335	6519	0.335	6884	0.912	0.911	99.7531	0.33
2.308-2.372	0.311	386	0.302	6356	0.302	6747	0.93	0.934	99.9259	0.296
2.372-2.44	0.306	335	0.292	6233	0.293	6574	0.936	0.944	99.9087	0.281
2.44-2.515	0.288	374	0.274	6016	0.275	6396	0.951	0.954	99.9062	0.26
2.515-2.598	0.271	319	0.257	5843	0.258	6167	0.953	0.96	99.9189	0.238
2.598-2.689	0.296	286	0.246	5701	0.248	6005	0.954	0.967	99.7002	0.224
2.689-2.79	0.289	235	0.236	5539	0.239	5782	0.957	0.97	99.8616	0.212
2.79-2.904	0.264	300	0.222	5277	0.224	5580	0.96	0.973	99.9462	0.198
2.904-3.033	0.255	263	0.218	5078	0.22	5345	0.958	0.971	99.9252	0.195
3.033-3.181	0.241	263	0.198	4865	0.2	5135	0.963	0.976	99.8637	0.182
3.181-3.353	0.249	240	0.209	4628	0.211	4871	0.961	0.974	99.9384	0.198
3.353-3.556	0.247	238	0.202	4378	0.204	4635	0.965	0.978	99.5901	0.197
3.556-3.801	0.228	226	0.203	4132	0.205	4373	0.973	0.981	99.657	0.204
3.801-4.105	0.196	252	0.186	3798	0.187	4053	0.978	0.983	99.926	0.192
4.105-4.496	0.174	194	0.161	3578	0.162	3780	0.982	0.985	99.7884	0.176
4.496-5.025	0.172	192	0.146	3210	0.148	3417	0.981	0.987	99.561	0.164
5.025-5.799	0.221	137	0.192	2882	0.193	3041	0.968	0.978	99.2766	0.215
5.799-7.095	0.244	124	0.216	2471	0.217	2599	0.967	0.973	99.8461	0.241
7.095-10.001	0.189	99	0.172	1949	0.173	2057	0.979	0.982	99.5625	0.209
10.001-88.672	0.218	63	0.236	1123	0.235	1215	0.967	0.962	97.6132	0.315

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	1.3891	1.1914	-0.5	3.4871	-0.5047	0.7384	0.0033	-0.0497	-0.0902	0.3227	-0.0038	-0.3258	-0.1225	0.2597	0.0005	0.0641	-0.0401	-0.0306	0.1564	-0.0173	0.2192	39.6046	-40.2346	-43.2689
2	3.2644	0.3806	-1.8711	0.861	-0.3524	1.8087	-0.1921	0.271	-0.4259	-0.0128	0.0841	0.1888	0.0506	-0.4473	0.108	0.0439	0.0129	-0.0204	0.1394	0.0024	0.3949	5.5075	-60.7062	-33.4187
3	1.4566	-0.1279	0.2507	2.8278	-1.7836	2.4975	-0.0131	-0.5119	-0.0438	0.5455	-0.3091	-0.8891	-0.0998	0.6434	0.3221	0.2384	-0.0341	-0.1371	0.5086	0.0421	0.446	28.4191	-44.407	-15.2489
4	1.8553	0.2366	-0.3716	1.3392	-0.518	3.115	-0.0762	0.4376	0.1117	-0.153	0.0562	0.2394	0.1806	-0.4193	0.02	0.0256	-0.019	-0.033	0.2213	0.0201	0.2564	7.2298	-34.724	-48.6561

Refinement TLS group

Selection: ALL

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