PDB-6i55: Plasmodium falciparum dihydroorotate dehydrogenase (DHODH) co-cry...

ID or keywords:

Entry

Database: PDB / ID: 6i55

Title

Plasmodium falciparum dihydroorotate dehydrogenase (DHODH) co-crystallized with N-(2,2-Diphenylethyl)-4-hydroxy-1,2,5-thiadiazole-3-carboxamide

Components

Dihydroorotate dehydrogenase

Keywords

OXIDOREDUCTASE / dhodh / plasmodium falciparum / inhibitor complex

Function / homology

Function and homology information

dihydroorotate dehydrogenase (quinone) activity / dihydroorotate dehydrogenase (quinone) / 'de novo' UMP biosynthetic process / 'de novo' pyrimidine nucleobase biosynthetic process / mitochondrial inner membrane / nucleotide binding / plasma membrane
Similarity search - Function

Biological species

Plasmodium falciparum (malaria parasite P. falciparum)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.98 Å

Authors

Goyal, P. / Sainas, S. / Pippione, A.C. / Boschi, D. / Al-Kadaraghi, S.

Citation

Journal: Eur J Med Chem / Year: 2018
Title: Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies.
Authors: Pippione, A.C. / Sainas, S. / Goyal, P. / Fritzson, I. / Cassiano, G.C. / Giraudo, A. / Giorgis, M. / Tavella, T.A. / Bagnati, R. / Rolando, B. / Caing-Carlsson, R. / Costa, F.T.M. / ...

History

Deposition	Nov 12, 2018	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Dec 19, 2018	Provider: repository / Type: Initial release
Revision 1.1	May 15, 2024	Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2 Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	6i55.cif.gz	320.9 KB	Display	PDBx/mmCIF format
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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/i5/6i55 ftp://data.pdbj.org/pub/pdb/validation_reports/i5/6i55	HTTPS FTP

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Related structure data

Related structure data	6i4bC C: citing same article (ref.)
Similar structure data	5boo-1 6vtn-d 3i68-d 3o8a-d 6aje-3 3sfk-d 5mc8-d 4cqa-1 3i65-d 6e0b-d Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) 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

Deposited unit

A: Dihydroorotate dehydrogenase

B: Dihydroorotate dehydrogenase

hetero molecules

93.6 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Dihydroorotate dehydrogenase

hetero molecules

defined by author
46.8 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

B: Dihydroorotate dehydrogenase

hetero molecules

defined by author
46.8 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	50.842, 158.422, 62.252
Angle α, β, γ (deg.)	90.00, 106.56, 90.00
Int Tables number	4
Space group name H-M	P12₁1

#1: Protein	Dihydroorotate dehydrogenase Mass: 45852.461 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum) Gene: dhod / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q54A96
#2: Chemical	ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE Mass: 456.344 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C₁₇H₂₁N₄O₉P
#3: Chemical	ChemComp-ORO / OROTIC ACID Mass: 156.096 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₅H₄N₂O₄
#4: Chemical	ChemComp-DZB / N-(2,2-Diphenylethyl)-4-hydroxy-1,2,5-thiadiazole-3-carboxamide Mass: 325.385 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₇H₁₅N₃O₂S
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 344 / 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: 2.62 Å³/Da / Density % sol: 53.06 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion, sitting drop Details: 0.1 M Tris-HCl pH 7.5-9.5 35% (w/v) PEG4000 50 mM Na-formate PH range: 7.5-9.5

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.97 Å
Detector	Type: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 13, 2015
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.97 Å / Relative weight: 1
Reflection	Resolution: 1.948→48.733 Å / Num. obs: 68050 / % possible obs: 99 % / Redundancy: 1.9 % / Net I/σ(I): 12.02
Reflection shell	Resolution: 1.948→2.018 Å

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Processing

Software

Name	Classification
PHENIX	refinement
XDS	data reduction
SCALA	data scaling
PHASER	phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.98→48.733 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.03

	R_factor	Num. reflection	% reflection
R_free	0.2176	3207	4.93 %
R_work	0.1728	-	-
obs	0.175	64995	99.3 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å

Refinement step

Cycle: LAST / Resolution: 1.98→48.733 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	5921	0	130	344	6395

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.007	6175
X-RAY DIFFRACTION	f_angle_d	0.821	8326
X-RAY DIFFRACTION	f_dihedral_angle_d	5.509	4406
X-RAY DIFFRACTION	f_chiral_restr	0.053	919
X-RAY DIFFRACTION	f_plane_restr	0.005	1057

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
1.98-2.0096	0.3571	113	0.3204	2751	X-RAY DIFFRACTION	99
2.0096-2.041	0.3069	146	0.2802	2619	X-RAY DIFFRACTION	99
2.041-2.0744	0.2859	138	0.255	2713	X-RAY DIFFRACTION	99
2.0744-2.1102	0.274	138	0.2334	2645	X-RAY DIFFRACTION	99
2.1102-2.1486	0.2684	137	0.2145	2675	X-RAY DIFFRACTION	99
2.1486-2.1899	0.2453	139	0.1955	2699	X-RAY DIFFRACTION	100
2.1899-2.2346	0.2394	132	0.1914	2672	X-RAY DIFFRACTION	100
2.2346-2.2832	0.2668	155	0.1846	2679	X-RAY DIFFRACTION	99
2.2832-2.3363	0.2378	133	0.1802	2677	X-RAY DIFFRACTION	99
2.3363-2.3947	0.2414	138	0.183	2704	X-RAY DIFFRACTION	99
2.3947-2.4595	0.2026	155	0.1704	2643	X-RAY DIFFRACTION	99
2.4595-2.5318	0.2501	150	0.1685	2681	X-RAY DIFFRACTION	99
2.5318-2.6135	0.2231	130	0.167	2694	X-RAY DIFFRACTION	99
2.6135-2.7069	0.193	157	0.1635	2664	X-RAY DIFFRACTION	100
2.7069-2.8153	0.2181	140	0.1666	2698	X-RAY DIFFRACTION	100
2.8153-2.9434	0.2365	148	0.1749	2677	X-RAY DIFFRACTION	99
2.9434-3.0986	0.2401	117	0.181	2726	X-RAY DIFFRACTION	100
3.0986-3.2927	0.1908	131	0.1772	2668	X-RAY DIFFRACTION	99
3.2927-3.5468	0.2279	158	0.1713	2695	X-RAY DIFFRACTION	99
3.5468-3.9036	0.179	161	0.1657	2684	X-RAY DIFFRACTION	100
3.9036-4.4682	0.1929	132	0.1555	2698	X-RAY DIFFRACTION	100
4.4682-5.6281	0.221	123	0.1454	2712	X-RAY DIFFRACTION	99
5.6281-48.7477	0.2079	136	0.1707	2714	X-RAY DIFFRACTION	99

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	2.594	-1.5662	-0.28	6.1961	4.0095	5.532	0.1489	-0.4931	-0.7035	0.3272	0.2398	0.1903	0.9836	0.3454	-0.4073	0.8931	-0.0383	-0.2543	0.478	0.1052	0.6645	18.278	13.589	33.8412
2	5.1286	-1.2126	0.7704	2.9736	-0.6447	0.9842	0.1228	-0.1513	-0.5843	0.2032	0.1508	-0.5159	0.4069	0.8301	-0.1722	0.6927	0.045	-0.1631	0.3795	0.0009	0.5883	23.6225	22.929	28.4597
3	1.7789	0.4498	0.8885	2.3968	-0.1039	1.8674	0.2274	-0.1835	-0.3033	0.274	-0.073	-0.121	0.2892	-0.0221	-0.1344	0.4538	0.0066	-0.0491	0.2685	0.0346	0.2829	15.3508	32.4979	27.5983
4	4.1184	0.291	0.4673	6.2127	3.0521	6.2399	0.0876	0.1363	-0.2365	-0.1393	0.0524	-0.5522	-0.0456	0.3738	-0.1489	0.2937	0.0482	-0.0083	0.2339	0.0591	0.253	24.7944	39.275	23.1267
5	3.7016	-0.2305	0.562	2.52	0.3803	2.0238	-0.1072	-0.021	0.2486	0.0262	0.0558	-0.1094	-0.3325	0.0488	0.0329	0.4146	0.0233	-0.0164	0.2531	0.0046	0.2238	15.4921	48.4743	21.0895
6	1.7002	-0.2091	0.7588	2.835	-0.9141	3.7529	0.1699	-0.3317	-0.1992	0.284	-0.0084	0.4174	0.1706	-0.5587	-0.1775	0.353	-0.0391	0.0264	0.4591	0.0376	0.3409	0.2208	35.552	24.3033
7	2.1474	0.3278	1.5354	1.7445	1.2803	3.5084	0.5095	-0.1049	-0.5783	-0.1828	-0.0032	0.29	0.7677	-0.3628	-0.4613	0.5877	-0.0555	-0.1287	0.2957	0.0191	0.482	5.3129	21.1223	15.4508
8	3.0298	-0.9432	1.1182	4.019	-0.8209	3.738	0.07	-0.3461	0.4889	0.2254	-0.1509	-0.0467	-0.5623	-0.035	0.0646	0.5553	-0.037	-0.0749	0.4229	-0.0988	0.4473	31.9973	80.2372	63.9136
9	1.258	-0.0207	0.7146	1.9917	-0.0433	2.4803	0.0478	0.0054	0.0255	-0.0312	-0.0768	-0.1019	0.1181	0.143	0.0154	0.2297	0.0029	0.0025	0.2579	0.0209	0.2642	29.971	57.999	55.0173
10	8.7339	3.6391	3.3767	3.7575	2.1768	3.501	-0.176	0.3085	0.2062	-0.3323	0.0563	-0.6693	-0.0039	0.764	0.0231	0.2668	-0.0032	0.0633	0.5476	0.0968	0.5177	45.0722	63.9359	49.3306
11	1.68	-0.1772	1.0202	2.3561	0.6731	2.4911	-0.116	0.257	0.4114	-0.2993	-0.1272	-0.0607	-0.5278	0.2538	0.2349	0.4025	-0.049	0.0009	0.3249	0.0911	0.339	31.2904	71.5531	41.5972

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 159 through 180 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 181 through 205 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 206 through 282 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 283 through 320 )
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 321 through 435 )
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 436 through 528 )
7	X-RAY DIFFRACTION	7	chain 'A' and (resid 529 through 567 )
8	X-RAY DIFFRACTION	8	chain 'B' and (resid 159 through 205 )
9	X-RAY DIFFRACTION	9	chain 'B' and (resid 206 through 449 )
10	X-RAY DIFFRACTION	10	chain 'B' and (resid 450 through 474 )
11	X-RAY DIFFRACTION	11	chain 'B' and (resid 475 through 566 )

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