PDB-5scq: Crystal Structure of Dihydrofolate Reductase from Mycobacterium t...

ID or keywords:

Entry

Database: PDB / ID: 5scq

Title

Crystal Structure of Dihydrofolate Reductase from Mycobacterium tuberculosis bound to NADP and SDDC Inhibitor SDDC-614

Components

Dihydrofolate reductase

Keywords

OXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Mycobacterium tuberculosis / DHFR / NADP / Folate / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID

Function / homology

Function and homology information

NADP+ binding / dihydrofolate metabolic process / dihydrofolate reductase / dihydrofolate reductase activity / folic acid metabolic process / tetrahydrofolate biosynthetic process / one-carbon metabolic process / NADP binding / cytosol
Similarity search - Function

Biological species

Mycobacterium tuberculosis H37Rv (bacteria)

Method

X-RAY DIFFRACTION /

MOLECULAR REPLACEMENT / Resolution: 1.65 Å

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID)

Funding support

United States, 1items

Citation

Journal: to be published
Title: Crystal Structure of Dihydrofolate Reductase from Mycobacterium tuberculosis bound to NADP and SDDC Inhibitor SDDC-614
Authors: Mayclin, S.J. / Fairman, J.W. / Dranow, D.M. / Conrady, D.G. / Fox III, D. / Lukacs, C.M. / Lorimer, D.D. / Horanyi, P.S. / Edwards, T.E. / Abendroth, J.

History

Deposition	Dec 20, 2021	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Feb 9, 2022	Provider: repository / Type: Initial release
Revision 1.1	Mar 2, 2022	Group: Other / Structure summary Category: pdbx_SG_project / pdbx_database_status / struct_keywords Item: _pdbx_database_status.SG_entry / _struct_keywords.text
Revision 1.2	May 22, 2024	Group: Data collection / Category: chem_comp_atom / chem_comp_bond

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	5scq.cif.gz	87.1 KB	Display	PDBx/mmCIF format
PDB format	pdb5scq.ent.gz	64.1 KB	Display	PDB format
PDBx/mmJSON format	5scq.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	5scq_validation.pdf.gz	952.7 KB	Display	wwPDB validaton report
Full document	5scq_full_validation.pdf.gz	954.8 KB	Display
Data in XML	5scq_validation.xml.gz	11.2 KB	Display
Data in CIF	5scq_validation.cif.gz	15.8 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/sc/5scq ftp://data.pdbj.org/pub/pdb/validation_reports/sc/5scq	HTTPS FTP

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Group deposition

ID	G_1002223 (26 entries) 5scm 5scn 5sco 5scp 5scq 5scr 5scs 5sct 5scu 5scv
Title	DHFR structures, SSGCID
Type	ground state
Description	human and M. tuberculosis DHFR structures bound to ligands

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Related structure data

Similar structure data	5scp-2 5scs-d 5u26-d 2w9t-1 6r5c-1 1nwa-d 6r57-2 5scn-d 2ioi-d 1s17-2 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	#34 - Oct 2002 Dihydrofolate Reductase similarity (8)

Deposited unit

A: Dihydrofolate reductase

hetero molecules

21 kDa, 1 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)	29.280, 66.880, 77.360
Angle α, β, γ (deg.)	90.000, 90.000, 90.000
Int Tables number	19
Space group name H-M	P2₁2₁2₁

Details

biological unit is a monomer, the same as asu

#1: Protein	Dihydrofolate reductase Mass: 19832.365 Da / Num. of mol.: 1 / Fragment: MtDHFR Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mycobacterium tuberculosis H37Rv (bacteria) Strain: ATCC 25618 / H37Rv / Gene: folA, dfrA, Rv2763c, MTV002.28c / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P9WNX1, dihydrofolate reductase
#2: Chemical	ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₁H₂₈N₇O₁₇P₃
#3: Chemical	ChemComp-GXC / N-[2-(2-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)ethanesulfonyl]acetamide Mass: 437.513 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₁₉H₂₇N₅O₅S / Feature type: SUBJECT OF INVESTIGATION
#4: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 174 / 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: 1.91 Å³/Da / Density % sol: 35.59 %
Crystal grow	Temperature: 289 K / Method: vapor diffusion, sitting drop Details: Wizard 3/4 D11 (267569d11): 30% PEG5000 MME, 200mM Ammonium sulfate, 100mM MES/Sodium hydroxide pH6.5, 3.5mM EBSI5522, protein concentration 40.69mg/mL, cryo 10% EG, puck uhg3-3

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Data collection

Diffraction

Mean temperature: 100 K

Diffraction source

Source: Rotating Copper Anode / Type: FRE+ Superbright / Wavelength: 1.5418 Å

Detector

Type: Saturn 944+ / Detector: CCD / Date: Dec 28, 2015

Radiation

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

Radiation wavelength

Wavelength: 1.5418 Å / Relative weight: 1

Reflection

Resolution: 1.65→50 Å / Num. obs: 18741 / % possible obs: 98.7 % / Observed criterion σ(I): -3 / B_iso Wilson estimate: 21.631 Å² / R_merge F obs: 1 / R_merge(I) obs: 0.057 / R_rim(I) all: 0.06 / Net I/σ(I): 29.4 / Num. measured all: 234112

Reflection shell

Resolution (Å)	Highest resolution (Å)	R_merge F obs	R_merge(I) obs	Mean I/σ(I) obs	Num. measured obs	Num. possible	Num. unique obs	R_rim(I) all	% possible all
1.65-1.69		0.812	0.459	2.77	4548	1370	1176	0.526	85.8
1.69-1.74		0.885	0.408	3.89	7027	1351	1294	0.449	95.8
1.74-1.79		0.946	0.375	5.37	10476	1297	1297	0.401	100
1.79-1.84		0.968	0.273	7.36	10886	1285	1285	0.291	100
1.84-1.91		0.981	0.225	9.13	10832	1224	1224	0.239	100
1.91-1.97		0.99	0.167	12.3	11241	1215	1215	0.177	100
1.97-2.05		0.993	0.142	14.94	11030	1142	1142	0.15	100
2.05-2.13		0.996	0.122	18.57	11669	1108	1108	0.129	100
2.13-2.22		0.997	0.099	25.43	13943	1078	1078	0.104	100
2.22-2.33		0.998	0.096	27.97	14149	1012	1012	0.099	100
2.33-2.46		0.999	0.081	32.94	14616	992	992	0.084	100
2.46-2.61		0.999	0.073	37.61	14883	926	926	0.075	100
2.61-2.79		0.999	0.072	41.45	15784	877	877	0.074	100
2.79-3.01		0.999	0.058	54.04	17294	823	823	0.059	100
3.01-3.3		1	0.046	65.31	15896	765	765	0.047	100
3.3-3.69		1	0.041	76.9	14340	698	698	0.042	100
3.69-4.26		1	0.034	87.44	12432	618	618	0.035	100
4.26-5.22		1	0.03	89.39	10481	531	531	0.031	100
5.22-7.38		1	0.037	73.31	8382	431	431	0.038	100
	7.38	1	0.029	87.51	4203	252	249	0.03	98.8

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Processing

Software

Name	Version	Classification
XDS		data reduction
XSCALE		data scaling
PHENIX	dev_2271	refinement
PDB_EXTRACT	3.11	data extraction
PHENIX		model building
Coot		model building
PHENIX		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.65→33.483 Å / Occupancy max: 1 / Occupancy min: 0.3 / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 16.6 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.187	1862	9.94 %
R_work	0.1524	16879	-
obs	0.1557	18741	98.66 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL

Displacement parameters

B_iso max: 66.8 Å² / B_iso mean: 17.7267 Å² / B_iso min: 5.38 Å²

Refinement step

Cycle: LAST / Resolution: 1.65→33.483 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	1272	0	78	174	1524

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.006	1399
X-RAY DIFFRACTION	f_angle_d	1.06	1920
X-RAY DIFFRACTION	f_chiral_restr	0.057	204
X-RAY DIFFRACTION	f_plane_restr	0.006	240
X-RAY DIFFRACTION	f_dihedral_angle_d	20.047	787

LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 13

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Num. reflection all	% reflection obs (%)
1.6498-1.6944	0.2722	132	0.218	1096	1228	86
1.6944-1.7443	0.2366	139	0.1907	1243	1382	96
1.7443-1.8006	0.2511	138	0.1716	1301	1439	100
1.8006-1.8649	0.1872	147	0.1708	1277	1424	100
1.8649-1.9396	0.2245	162	0.1538	1291	1453	100
1.9396-2.0278	0.1857	156	0.1503	1278	1434	100
2.0278-2.1347	0.1886	147	0.1487	1290	1437	100
2.1347-2.2685	0.1713	125	0.149	1332	1457	100
2.2685-2.4436	0.1852	130	0.1535	1338	1468	100
2.4436-2.6894	0.2086	142	0.1523	1317	1459	100
2.6894-3.0783	0.1902	139	0.1582	1329	1468	100
3.0783-3.8774	0.1665	155	0.1402	1345	1500	100
3.8774-33.4903	0.1543	150	0.1395	1442	1592	100

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	0.5561	0.1905	-0.2333	3.7874	3.8169	4.7735	-0.0254	0.1005	-0.0794	-0.1371	-0.1591	-0.0047	0.0747	-0.263	0.2093	0.1062	0.0132	0.0126	0.102	-0.0311	0.0911	-10.6701	-11.7648	6.1601
2	2.3045	-1.6011	0.9515	2.9399	-0.886	1.7368	0.0429	-0.0445	0.0817	0.1956	0.0403	-0.0442	-0.2768	0.0829	-0.0543	0.1423	-0.0379	-0.0021	0.0872	-0.0253	0.1067	-8.5	2.7815	21.5454
3	1.8889	-1.1587	0.1598	2.9591	1.2711	7.5883	0.2559	-0.1935	-0.0391	0.0352	-0.0065	-0.3207	-0.1511	0.3145	-0.2301	0.0713	-0.0035	-0.0031	0.174	0.0197	0.156	0.9562	-6.2224	13.5554
4	3.0235	-0.5125	-0.1571	2.1277	-0.1388	1.7339	0.0762	0.039	0.1028	0.0438	-0.138	-0.0809	0.0053	0.4805	0.0043	0.0749	0.0258	0.002	0.1442	0.0108	0.0564	-7.1475	2.2225	5.0577
5	3.3245	0.7674	-0.0421	2.363	0.4522	4.1239	0.0803	0.003	0.2486	-0.0022	-0.1713	-0.4063	-0.3208	0.4694	0.077	0.1068	-0.02	-0.0032	0.2419	0.0548	0.178	0.8271	3.8591	5.6857
6	6.1475	-2.8762	0.4687	5.637	-0.1378	3.7531	0.1219	0.1775	0.2987	-0.1022	-0.0554	0.0427	-0.3046	0.199	-0.0401	0.1081	0.0006	0.0141	0.1161	0.0198	0.0748	-9.9883	7.2303	-1.2468
7	1.8718	-0.7029	-0.802	7.7802	-0.7571	0.4777	0.0008	0.3353	-0.0724	-0.4324	-0.0974	0.3518	0.2989	0.0173	0.0879	0.1812	0.0302	-0.03	0.1804	0.0012	0.1336	-13.4716	-2.4872	-3.7377
8	1.2059	0.7659	0.2526	2.3582	0.7733	2.2565	0.1197	0.0563	-0.033	-0.0916	-0.0286	0.0739	0.0981	0.0319	-0.0797	0.0658	0.0206	0.001	0.0673	-0.0057	0.0739	-13.0895	-6.9547	9.9381
9	5.5983	-3.2822	4.1199	2.2174	-2.7652	3.6215	-0.2085	-0.3128	0.1186	0.2636	0.168	0.2415	-0.3112	-0.0523	0.0958	0.2543	0.034	-0.0019	0.1614	-0.034	0.1502	-13.8239	3.5452	26.4309
10	0.6088	1.4516	-0.0098	3.616	0.4196	1.8765	0.0016	-0.2687	-0.0919	0.6438	0.1034	0.3727	0.2075	0.0184	-0.0485	0.1432	-0.0058	-0.0135	0.0911	0.0243	0.215	-17.5462	-11.9527	16.9308
11	7.3408	3.3917	0.6162	6.7108	1.105	4.2165	0.1061	0.126	-0.0657	0.0526	-0.0675	-0.3927	0.147	0.0747	-0.0698	0.1279	-0.0052	-0.0277	0.1447	0.0075	0.1058	0.4438	-8.3029	27.9438
12	7.9091	2.28	8.0063	1.3448	2.2254	8.374	0.3892	-0.0551	-0.3213	0.0778	-0.0703	-0.0067	0.4413	-0.1019	-0.3083	0.1357	-0.006	-0.0274	0.1159	0.0087	0.1364	-10.5504	-14.3211	17.6655

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details	Auth asym-ID
1	X-RAY DIFFRACTION	1	chain 'A' and (resid -6 through 9 )	A
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 10 through 24 )	A
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 25 through 35 )	A
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 36 through 49 )	A
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 50 through 60 )	A
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 61 through 76 )	A
7	X-RAY DIFFRACTION	7	chain 'A' and (resid 77 through 89 )	A
8	X-RAY DIFFRACTION	8	chain 'A' and (resid 90 through 115 )	A
9	X-RAY DIFFRACTION	9	chain 'A' and (resid 116 through 125 )	A
10	X-RAY DIFFRACTION	10	chain 'A' and (resid 126 through 139 )	A
11	X-RAY DIFFRACTION	11	chain 'A' and (resid 140 through 150 )	A
12	X-RAY DIFFRACTION	12	chain 'A' and (resid 151 through 159 )	A

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