PDB-4hwt: Crystal structure of human Threonyl-tRNA synthetase bound to a no...

ID or keywords:

Entry

Database: PDB / ID: 4hwt

Title

Crystal structure of human Threonyl-tRNA synthetase bound to a novel inhibitor

Components

Threonine--tRNA ligase, cytoplasmic

Keywords

Ligase/Ligase Inhibitor / aminoacyl-tRNA synthetase / protein-inhibitor complex / Ligase-Ligase Inhibitor complex

Function / homology

Function and homology information

threonine-tRNA ligase / threonyl-tRNA aminoacylation / threonine-tRNA ligase activity / Cytosolic tRNA aminoacylation / tRNA binding / zinc ion binding / extracellular exosome / ATP binding / identical protein binding / cytosol
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT /

molecular replacement / Resolution: 2.3 Å

Authors

Hilgers, M.T.

Citation

Journal: J.Med.Chem. / Year: 2013
Title: Identification of bacteria-selective threonyl-tRNA synthetase substrate inhibitors by structure-based design.
Authors: Teng, M. / Hilgers, M.T. / Cunningham, M.L. / Borchardt, A. / Locke, J.B. / Abraham, S. / Haley, G. / Kwan, B.P. / Hall, C. / Hough, G.W. / Shaw, K.J. / Finn, J.

History

Deposition	Nov 8, 2012	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Sep 18, 2013	Provider: repository / Type: Initial release

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	4hwt.cif.gz	339.8 KB	Display	PDBx/mmCIF format
PDB format	pdb4hwt.ent.gz	288.9 KB	Display	PDB format
PDBx/mmJSON format	4hwt.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	4hwt_validation.pdf.gz	957 KB	Display	wwPDB validaton report
Full document	4hwt_full_validation.pdf.gz	981.1 KB	Display
Data in XML	4hwt_validation.xml.gz	37 KB	Display
Data in CIF	4hwt_validation.cif.gz	51.5 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/hw/4hwt ftp://data.pdbj.org/pub/pdb/validation_reports/hw/4hwt	HTTPS FTP

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Related structure data

Related structure data	4hwoC 4hwpC 4hwrC 4hwsC C: citing same article (ref.)
Similar structure data	7cbg-d 7cbi-d 4hwr-d 4hwo-d 4hwp-d 6l2p-d 1evl-1 6olt-1 6l2q-d 4hws-d Search similar-shape structures by Omokage search (details) 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	#16 - Apr 2001 Aminoacyl-tRNA Synthetases similarity (21) #117 - Sep 2009 Xanthine Oxidoreductase similarity (1) #154 - Oct 2012 Citric Acid Cycle similarity (1) #82 - Oct 2006 Cytochrome p450 similarity (1) #241 - Jan 2020 Twenty Years of Molecules similarity (1)

Deposited unit

A: Threonine--tRNA ligase, cytoplasmic

B: Threonine--tRNA ligase, cytoplasmic

hetero molecules

97.8 kDa, 2 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)	73.897, 73.897, 357.587
Angle α, β, γ (deg.)	90.000, 90.000, 90.000
Int Tables number	92
Space group name H-M	P4₁2₁2

#1: Protein	Threonine--tRNA ligase, cytoplasmic / Threonyl-tRNA synthetase / ThrRS Mass: 48476.098 Da / Num. of mol.: 2 / Fragment: UNP residues 321-723 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TARS / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-AI / References: UniProt: P26639, threonine-tRNA ligase
#2: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical	ChemComp-1B2 / N-{[3-(2H-indazol-5-yl)phenyl]sulfonyl}-L-threoninamide Mass: 374.414 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₇H₁₈N₄O₄S
#4: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 345 / Source method: isolated from a natural source / Formula: H₂O

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Experiment

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

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Sample preparation

Crystal	Density Matthews: 2.52 Å³/Da / Density % sol: 51.14 %
Crystal grow	Temperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.9 Details: PEG 3350, sodium citrate, pH 7.9, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

Diffraction source

Source:

SYNCHROTRON / Site:

ALS

/ Beamline: 8.2.2 / Wavelength: 1 Å

Detector

Type: MARMOSAIC 325 mm CCD / Detector: CCD

Radiation

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

Radiation wavelength

Wavelength: 1 Å / Relative weight: 1

Reflection

Resolution: 2.3→42.19 Å / Num. obs: 44551 / % possible obs: 97.9 % / Redundancy: 7.93 % / R_merge(I) obs: 0.094 / Χ²: 0.94 / Net I/σ(I): 10.5 / Scaling rejects: 10931

Reflection shell

Diffraction-ID: 1

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Mean I/σ(I) obs	Num. measured all	Num. unique all	Χ²	% possible all
2.3-2.38	6.84	0.303	5.3	26623	3721	1.14	83.2
2.38-2.48	7.83	0.302	5.6	35820	4348	1.12	98.4
2.48-2.59	9.01	0.267	6.2	41240	4450	1.04	100
2.59-2.73	9.02	0.235	6.4	41249	4478	1	100
2.73-2.9	8.95	0.21	7.4	41188	4498	1	100
2.9-3.12	8.75	0.168	9.1	40304	4501	0.94	100
3.12-3.44	8.44	0.124	11.6	38952	4524	0.83	100
3.44-3.93	7.72	0.095	14	36263	4570	0.78	99.5
3.93-4.95	6.86	0.065	19.3	32646	4600	0.74	99.1
4.95-42.19	5.91	0.049	23.5	30078	4861	0.77	98.7

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Phasing

Phasing

Method:

molecular replacement

Phasing MR

Model details: Phaser MODE: MR_AUTO

	Highest resolution	Lowest resolution
Rotation	2.5 Å	42.19 Å
Translation	2.5 Å	42.19 Å

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Processing

Software

Name	Version	Classification
d*TREK	9.9.9.1LDz	data reduction
PHASER	2.3.0	phasing
REFMAC	5.6.0117	refinement
PDB_EXTRACT	3.11	data extraction
d*TREK		data scaling

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 2.3→42.19 Å / Cor.coef. F_o:F_c: 0.949 / Cor.coef. F_o:F_c free: 0.919 / Occupancy max: 1 / Occupancy min: 1 / SU B: 14.494 / SU ML: 0.176 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.342 / ESU R Free: 0.246 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES: RESIDUAL ONLY

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2566	2240	5 %	RANDOM
R_work	0.2075	-	-	-
obs	0.2099	44479	97.75 %	-

Solvent computation

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

Displacement parameters

B_iso max: 69.82 Å² / B_iso mean: 44.939 Å² / B_iso min: 2 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	0.07 Å²	-0 Å²	-0 Å²
2-	-	0.07 Å²	0 Å²
3-	-	-	-0.14 Å²

Refinement step

Cycle: LAST / Resolution: 2.3→42.19 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	6573	0	54	345	6972

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.011	0.019	6791
X-RAY DIFFRACTION	r_angle_refined_deg	1.547	1.95	9159
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.59	5	794
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	35.247	23.398	362
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	20.735	15	1199
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	20.411	15	60
X-RAY DIFFRACTION	r_chiral_restr	0.109	0.2	946
X-RAY DIFFRACTION	r_gen_planes_refined	0.007	0.021	5254

LS refinement shell

Resolution: 2.3→2.36 Å / Total num. of bins used: 20

	R_factor	Num. reflection	% reflection
R_free	0.318	107	-
R_work	0.27	2341	-
all	-	2448	-
obs	-	-	80.95 %

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	0.3378	-0.06	0.0935	0.2755	0.0157	0.2079	-0.04	-0.0937	0.0251	0.0057	-0.0189	0.0319	-0.0656	-0.1322	0.059	0.3267	-0.0004	-0.0063	0.3878	-0.0005	0.3429	10.0996	-34.2187	-24.9827
2	2.7765	-2.6865	-6.4734	9.9166	2.0288	17.5485	-0.1315	0.2668	0.2233	-0.1283	0.6038	-0.135	0.6383	-1.0882	-0.4723	0.1169	-0.0459	0.0179	0.6856	0.0068	0.3162	0.1114	-35.3874	-4.807
3	0.3384	-0.038	0.0652	0.236	-0.1156	0.5613	-0.0055	-0.1746	0.0863	0.1005	-0.0036	0.0272	-0.0949	-0.2387	0.0091	0.3249	0.0131	-0.0027	0.4254	-0.0375	0.3193	10.9817	-27.5519	-12.2806
4	2.1369	5.9994	-5.5784	22.6521	-12.779	16.1946	0.1615	-0.0528	0.0042	0.4086	-0.4107	0.2123	-0.4735	-0.3333	0.2492	0.2218	0.1523	0.0891	0.5789	-0.2243	0.3648	5.9383	-12.9358	-0.7168
5	2.3535	0.5836	1.0504	5.2904	-2.5993	3.3183	-0.3526	-0.3393	0.3626	0.1053	0.2268	0.087	-0.4047	-0.6223	0.1259	0.314	0.1434	0.0464	0.3959	-0.0906	0.356	3.3882	-13.6088	-12.1669
6	7.2184	-0.3154	4.2331	0.7944	-0.7349	2.8966	-0.0542	-0.6188	0.458	-0.0728	-0.1443	0.055	0.0656	-0.3451	0.1985	0.3046	0.0521	0.0254	0.4539	-0.0138	0.4176	1.2529	-17.7004	-27.1074
7	0.4859	-0.0935	0.068	0.8096	0.8605	4.6293	-0.2504	-0.3779	0.1782	0.2394	0.0731	0.0413	-0.0744	-0.6642	0.1772	0.3709	0.1025	-0.0076	0.5752	-0.0864	0.2694	14.0234	-24.7859	0.1257
8	1.6539	-17.2272	-3.425	180.4594	35.9486	7.166	0.1449	0.0176	-0.2953	0.0896	-1.1443	3.9021	0.0083	-0.3402	0.9994	0.0435	0.1932	-0.094	1.5999	-0.7576	0.7928	27.1548	-19.7684	7.9991
9	0.7219	-0.1357	1.1285	1.0701	0.6511	2.8038	-0.1702	-0.1557	0.1938	0.0923	-0.1469	0.1718	-0.2209	-0.3959	0.3171	0.3173	0.0348	-0.0177	0.3692	-0.0649	0.3587	13.0781	-24.2998	-11.224
10	0.8463	-0.1111	-1.2266	0.1699	0.1629	1.8743	-0.0909	-0.0651	-0.0493	-0.1032	0.0063	0.1122	-0.0157	0.0695	0.0846	0.3558	0.0122	-0.0298	0.3259	0.0025	0.3613	14.9868	-29.9926	-46.5767
11	1.0614	-0.117	0.2763	0.7733	-0.148	1.6222	0.0099	0.0422	-0.0407	-0.1434	-0.0169	-0.047	-0.0108	0.0095	0.007	0.3528	0.0058	-0.0212	0.3343	0.0115	0.3237	18.402	-28.5809	-54.8129
12	7.9815	-1.9567	-10.3247	0.9464	3.4754	15.2791	0.5423	-0.2948	0.3902	-0.1168	-0.0739	-0.1031	-0.6324	0.1112	-0.4683	0.3253	0.0011	0.0395	0.2909	-0.0026	0.4154	22.1407	-19.6605	-40.9951
13	14.8779	3.1104	-1.96	11.5081	9.338	9.011	0.663	0.1991	-0.3994	-1.4847	-1.2897	0.6086	-1.5339	-1.1988	0.6266	0.7255	0.2581	-0.0742	0.7495	0.0683	0.6954	4.7533	-24.671	-14.7581
14	1.4332	-0.1324	-0.2922	0.5495	0.11	1.1877	0.039	-0.217	0.047	0.0084	-0.0376	-0.0372	0.0089	0.0535	-0.0014	0.3399	-0.0028	-0.0222	0.3705	0.024	0.3192	27.2613	-41.5226	-11.2927
15	0.3735	-0.0029	-0.0126	0.4049	0.2825	0.2255	0.0304	-0.1113	-0.0798	-0.0418	-0.0542	0.0137	0.0571	-0.0801	0.0238	0.3118	-0.0571	-0.0146	0.3906	0.0262	0.3638	8.4272	-49.9859	-28.8
16	0.6462	0.0557	0.1891	0.1779	0.2612	0.409	0.0587	-0.0198	-0.0842	0.0349	-0.0122	-0.0412	0.102	-0.035	-0.0465	0.3599	-0.0327	-0.0023	0.3277	0.0242	0.3849	22.3019	-52.4669	-28.7183
17	2.1705	0.7133	0.7966	1.9734	0.4891	1.2443	0.1055	-0.0816	-0.6654	-0.0208	-0.0385	-0.0865	0.3248	0.0072	-0.067	0.3545	-0.0079	-0.0131	0.2115	0.0196	0.444	22.2179	-69.076	-33.0832
18	2.6751	1.7767	1.6246	1.5155	1.0492	1.0074	0.1999	-0.3707	-0.0851	0.1836	-0.0974	0.0159	0.1919	-0.2173	-0.1025	0.4041	-0.0328	-0.0201	0.3552	0.0695	0.4079	23.0452	-61.8752	-27.5762
19	0.0514	-0.1557	-0.1031	0.5734	0.4366	0.8198	-0.0152	0.0174	-0.0542	0.0597	0.0453	0.0196	0.2701	0.0155	-0.0301	0.3646	-0.0404	-0.0082	0.3442	0.0289	0.4161	18.2947	-58.6198	-31.2788
20	29.9934	0.5133	9.8767	10.2521	1.298	3.4173	-0.1023	0.5416	-0.4084	-0.2129	0.151	-1.0808	-0.1452	0.2815	-0.0488	0.291	-0.09	-0.07	0.6093	0.0945	0.5041	6.6363	-57.1197	-55.8752
21	0.7125	0.5446	1.5296	0.4437	1.1758	3.7499	0.0787	-0.1983	-0.0749	-0.0103	-0.0991	-0.0879	0.0593	-0.3045	0.0203	0.3356	-0.0234	-0.0084	0.3388	-0.0027	0.3919	17.5123	-54.302	-32.6752
22	0.6133	0.7496	-0.1167	1.4297	0.1316	0.1715	0.0605	-0.0705	-0.0526	0.0501	-0.0811	-0.0337	-0.0257	0.047	0.0207	0.3624	-0.0063	-0.0211	0.3519	0.0321	0.3428	38.692	-29.7568	-17.3452
23	0.6558	0.1724	-0.1961	0.6278	0.0232	1.1702	0.0706	-0.0264	-0.059	0.014	-0.0384	-0.0548	-0.1134	0.0817	-0.0322	0.3608	-0.0445	-0.0174	0.3531	0.012	0.315	46.894	-25.0885	-16.8838
24	6.2749	0.8795	-1.1054	13.5872	-2.8039	2.0579	-0.3468	0.6128	0.2289	-0.7172	0.2404	-0.1459	-0.054	-0.0374	0.1065	0.3451	-0.0547	0.0179	0.3903	0.0241	0.2523	40.1712	-33.2776	-30.6715
25	1.9874	8.2536	-2.3417	69.4541	-27.8356	12.0875	0.2013	-0.65	-0.6601	0.4402	-1.0162	-2.5157	-0.1493	-0.0777	0.8148	0.3588	-0.062	0.1472	0.6464	-0.0907	0.5503	48.9699	-34.1939	-27.8223
26	71.1952	-46.7657	7.7104	35.565	-7.7625	2.3421	-1.5766	-2.2297	-0.0032	1.0226	1.4612	-0.093	-0.1008	-0.213	0.1154	0.598	0.0361	0.0071	0.4329	0.0044	0.6678	20.7913	-57.6967	-25.0561

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	A	354 - 420
2	X-RAY DIFFRACTION	2	A	421 - 428
3	X-RAY DIFFRACTION	3	A	429 - 540
4	X-RAY DIFFRACTION	4	A	541 - 555
5	X-RAY DIFFRACTION	5	A	556 - 580
6	X-RAY DIFFRACTION	6	A	581 - 593
7	X-RAY DIFFRACTION	7	A	594 - 609
8	X-RAY DIFFRACTION	8	A	610 - 615
9	X-RAY DIFFRACTION	9	A	616 - 632
10	X-RAY DIFFRACTION	10	A	633 - 671
11	X-RAY DIFFRACTION	11	A	672 - 737
12	X-RAY DIFFRACTION	12	A	738 - 752
13	X-RAY DIFFRACTION	13	A	802
14	X-RAY DIFFRACTION	14	B	354 - 391
15	X-RAY DIFFRACTION	15	B	392 - 462
16	X-RAY DIFFRACTION	16	B	463 - 527
17	X-RAY DIFFRACTION	17	B	528 - 569
18	X-RAY DIFFRACTION	18	B	570 - 582
19	X-RAY DIFFRACTION	19	B	583 - 609
20	X-RAY DIFFRACTION	20	B	610 - 615
21	X-RAY DIFFRACTION	21	B	616 - 632
22	X-RAY DIFFRACTION	22	B	633 - 676
23	X-RAY DIFFRACTION	23	B	677 - 738
24	X-RAY DIFFRACTION	24	B	739 - 750
25	X-RAY DIFFRACTION	25	B	751 - 755
26	X-RAY DIFFRACTION	26	B	802

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