PDB-8r3u: Crystal structure of DHPS in complex with an inhibitor

ID or keywords:

Entry

Database: PDB / ID: 8r3u

Title

Crystal structure of DHPS in complex with an inhibitor

Components

Deoxyhypusine synthase

Keywords

TRANSFERASE / Protein-inhibitor complex

Function / homology

Function and homology information

deoxyhypusine synthase / peptidyl-lysine modification to peptidyl-hypusine / Hypusine synthesis from eIF5A-lysine / deoxyhypusine synthase activity / spermidine metabolic process / spermidine catabolic process / positive regulation of T cell proliferation / glucose homeostasis / translation / positive regulation of cell population proliferation ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.63 Å

Authors

Turnbull, A.P.

Funding support

1items

Citation

Journal: To Be Published
Title: Crystal structure of DHPS in complex with an inhibitor
Authors: Turnbull, A.P.

History

Deposition	Nov 10, 2023	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Nov 20, 2024	Provider: repository / Type: Initial release

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	8r3u.cif.gz	286.6 KB	Display	PDBx/mmCIF format
PDB format	pdb8r3u.ent.gz		Display	PDB format
PDBx/mmJSON format	8r3u.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/r3/8r3u ftp://data.pdbj.org/pub/pdb/validation_reports/r3/8r3u	HTTPS FTP

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Related structure data

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	#213 - Sep 2017 Sirtuins similarity (1) #263 - Nov 2021 Acetohydroxyacid Synthase similarity (1)

Deposited unit

AAA: Deoxyhypusine synthase

BBB: Deoxyhypusine synthase

CCC: Deoxyhypusine synthase

DDD: Deoxyhypusine synthase

hetero molecules

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

1

Idetical with deposited unit
defined by author

Unit cell

Length a, b, c (Å)	79.530, 107.852, 96.860
Angle α, β, γ (deg.)	90.000, 93.133, 90.000
Int Tables number	4
Space group name H-M	P12₁1

Noncrystallographic symmetry (NCS)

NCS domain:

ID	Ens-ID	Details
1	1	AAA
2	1	BBB
3	2	AAA
4	2	CCC
5	3	AAA
6	3	DDD
7	4	BBB
8	4	CCC
9	5	BBB
10	5	DDD
11	6	CCC
12	6	DDD

NCS domain segments:

Beg auth comp-ID: SER / Beg label comp-ID: SER

Dom-ID	Component-ID	Ens-ID	End auth comp-ID	End label comp-ID	Auth asym-ID	Label asym-ID	Auth seq-ID	Label seq-ID
1	1	1	PHE	PHE	AAA	A	28 - 362	29 - 363
2	2	1	PHE	PHE	BBB	B	28 - 362	29 - 363
3	3	2	MET	MET	AAA	A	28 - 363	29 - 364
4	4	2	MET	MET	CCC	C	28 - 363	29 - 364
5	5	3	PHE	PHE	AAA	A	28 - 362	29 - 363
6	6	3	PHE	PHE	DDD	D	28 - 362	29 - 363
7	7	4	PHE	PHE	BBB	B	28 - 362	29 - 363
8	8	4	PHE	PHE	CCC	C	28 - 362	29 - 363
9	9	5	PHE	PHE	BBB	B	28 - 362	29 - 363
10	10	5	PHE	PHE	DDD	D	28 - 362	29 - 363
11	11	6	PHE	PHE	CCC	C	28 - 362	29 - 363
12	12	6	PHE	PHE	DDD	D	28 - 362	29 - 363

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	Deoxyhypusine synthase Mass: 41025.367 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: DHPS / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P49366
#2: Chemical	ChemComp-XTQ / 2-[(2~{R})-1-azanyl-4-methyl-pentan-2-yl]-5-pyridin-3-yl-isoquinolin-1-one Mass: 321.416 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₂₀H₂₃N₃O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL Mass: 62.068 Da / Num. of mol.: 18 / Source method: obtained synthetically / Formula: C₂H₆O₂
#4: Chemical	ChemComp-DMS / DIMETHYL SULFOXIDE Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂H₆OS / Comment: DMSO, precipitant*YM
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 940 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	Y
Has protein modification	N

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Experiment

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

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Sample preparation

Crystal	Density Matthews: 2.53 Å³/Da / Density % sol: 51.34 %
Crystal grow	Temperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 20 % w/v PEG 3350, 0.2 M Ammonium chloride

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9537 Å
Detector	Type: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: May 22, 2023
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.9537 Å / Relative weight: 1
Reflection	Resolution: 1.63→72.01 Å / Num. obs: 202950 / % possible obs: 100 % / Redundancy: 7 % / CC_1/2: 0.997 / Net I/σ(I): 11.8
Reflection shell	Resolution: 1.63→1.66 Å / Mean I/σ(I) obs: 0.3 / Num. unique obs: 71272 / CC_1/2: 0.378 / % possible all: 100

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0267	refinement
xia2		data reduction
XSCALE		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.63→72.004 Å / Cor.coef. F_o:F_c: 0.976 / Cor.coef. F_o:F_c free: 0.965 / SU B: 3.529 / SU ML: 0.099 / Cross valid method: FREE R-VALUE / ESU R: 0.078 / ESU R Free: 0.081
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2105	1928	0.97 %
R_work	0.1798	196753	-
all	0.18	-	-
obs	-	198681	97.897 %

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: 38.484 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	2.808 Å²	0 Å²	0.483 Å²
2-	-	-0.104 Å²	-0 Å²
3-	-	-	-2.74 Å²

Refinement step

Cycle: LAST / Resolution: 1.63→72.004 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	9511	0	176	940	10627

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.01	0.013	9971
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.015	9476
X-RAY DIFFRACTION	r_angle_refined_deg	1.518	1.639	13518
X-RAY DIFFRACTION	r_angle_other_deg	1.42	1.574	21701
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.195	5	1251
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	31.247	23.438	480
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	14.284	15	1601
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	24.458	15	45
X-RAY DIFFRACTION	r_chiral_restr	0.082	0.2	1322
X-RAY DIFFRACTION	r_gen_planes_refined	0.009	0.02	11353
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	2307
X-RAY DIFFRACTION	r_nbd_refined	0.211	0.2	2078
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.17	0.2	9202
X-RAY DIFFRACTION	r_nbtor_refined	0.169	0.2	4989
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.08	0.2	4627
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.155	0.2	718
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.202	0.2	28
X-RAY DIFFRACTION	r_nbd_other	0.245	0.2	89
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.077	0.2	7
X-RAY DIFFRACTION	r_mcbond_it	3.448	3.876	4974
X-RAY DIFFRACTION	r_mcbond_other	3.447	3.875	4973
X-RAY DIFFRACTION	r_mcangle_it	4.753	5.773	6205
X-RAY DIFFRACTION	r_mcangle_other	4.752	5.773	6206
X-RAY DIFFRACTION	r_scbond_it	4.325	4.239	4997
X-RAY DIFFRACTION	r_scbond_other	4.324	4.24	4998
X-RAY DIFFRACTION	r_scangle_it	6.305	6.183	7303
X-RAY DIFFRACTION	r_scangle_other	6.305	6.184	7304
X-RAY DIFFRACTION	r_lrange_it	8.054	46.634	11580
X-RAY DIFFRACTION	r_lrange_other	8.051	46.556	11545
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.091	0.05	9666
X-RAY DIFFRACTION	r_ncsr_local_group_2	0.075	0.05	9693
X-RAY DIFFRACTION	r_ncsr_local_group_3	0.068	0.05	9381
X-RAY DIFFRACTION	r_ncsr_local_group_4	0.084	0.05	9814
X-RAY DIFFRACTION	r_ncsr_local_group_5	0.075	0.05	9547
X-RAY DIFFRACTION	r_ncsr_local_group_6	0.061	0.05	9506

Refine LS restraints NCS

Ens-ID	Dom-ID	Auth asym-ID	Refine-ID	Type	Rms dev position (Å)	Weight position
1	1	AAA	X-RAY DIFFRACTION	Local ncs	0.09059	0.05008
1	2	BBB	X-RAY DIFFRACTION	Local ncs	0.09059	0.05008
2	3	AAA	X-RAY DIFFRACTION	Local ncs	0.07469	0.05008
2	4	CCC	X-RAY DIFFRACTION	Local ncs	0.07469	0.05008
3	5	AAA	X-RAY DIFFRACTION	Local ncs	0.06785	0.05008
3	6	DDD	X-RAY DIFFRACTION	Local ncs	0.06785	0.05008
4	7	BBB	X-RAY DIFFRACTION	Local ncs	0.0838	0.05008
4	8	CCC	X-RAY DIFFRACTION	Local ncs	0.0838	0.05008
5	9	BBB	X-RAY DIFFRACTION	Local ncs	0.07496	0.05008
5	10	DDD	X-RAY DIFFRACTION	Local ncs	0.07496	0.05008
6	11	CCC	X-RAY DIFFRACTION	Local ncs	0.06136	0.05008
6	12	DDD	X-RAY DIFFRACTION	Local ncs	0.06136	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
1.63-1.672	0.502	125	0.53	12291	0.529	14937	0.05	0.046	83.1225	0.519
1.672-1.718	0.535	139	0.497	13155	0.498	14584	0.123	0.141	91.1547	0.489
1.718-1.768	0.452	127	0.45	13747	0.45	14264	0.235	0.28	97.2658	0.445
1.768-1.822	0.408	115	0.389	13509	0.389	13678	0.489	0.484	99.6052	0.387
1.822-1.882	0.31	131	0.338	13236	0.337	13370	0.516	0.531	99.9776	0.331
1.882-1.948	0.289	125	0.277	12810	0.278	12939	0.679	0.687	99.9691	0.263
1.948-2.021	0.22	130	0.23	12335	0.23	12466	0.847	0.848	99.992	0.209
2.021-2.104	0.231	134	0.197	11892	0.197	12027	0.894	0.91	99.9917	0.173
2.104-2.197	0.231	94	0.184	11438	0.184	11532	0.921	0.926	100	0.158
2.197-2.304	0.199	98	0.173	10915	0.173	11014	0.927	0.934	99.9909	0.148
2.304-2.429	0.225	87	0.165	10406	0.165	10493	0.929	0.946	100	0.139
2.429-2.576	0.208	101	0.147	9820	0.148	9921	0.943	0.961	100	0.125
2.576-2.753	0.185	97	0.141	9218	0.141	9315	0.955	0.968	100	0.123
2.753-2.974	0.141	79	0.14	8617	0.14	8696	0.974	0.971	100	0.125
2.974-3.257	0.195	89	0.15	7903	0.151	7992	0.953	0.965	100	0.138
3.257-3.64	0.201	80	0.158	7172	0.159	7252	0.956	0.964	100	0.15
3.64-4.202	0.16	69	0.139	6356	0.139	6425	0.967	0.971	100	0.136
4.202-5.142	0.19	50	0.13	5388	0.131	5438	0.96	0.974	100	0.134
5.142-7.253	0.205	31	0.187	4190	0.187	4221	0.952	0.959	100	0.19
7.253-72.004	0.197	27	0.178	2354	0.178	2381	0.956	0.958	100	0.2

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