PDB-6fcx: Structure of human 5,10-methylenetetrahydrofolate reductase (MTHFR)

ID or keywords:

Entry

Database: PDB / ID: 6fcx

Title

Structure of human 5,10-methylenetetrahydrofolate reductase (MTHFR)

Components

Methylenetetrahydrofolate reductase

Keywords

OXIDOREDUCTASE / one carbon metabolism /

rossmann fold /

S-adenosyl-methionine /

Structural Genomics /

Structural Genomics Consortium / SGC

Function / homology

Function and homology information

methylenetetrahydrofolate reductase (NADPH) / response to vitamin B2 / methylenetetrahydrofolate reductase (NADPH) activity /

methylenetetrahydrofolate reductase (NAD(P)H) activity / methionine metabolic process / modified amino acid binding / homocysteine metabolic process / heterochromatin organization / S-adenosylmethionine metabolic process / methionine biosynthetic process ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MAD / Resolution: 2.5 Å

Authors

Kopec, J. / Bezerra, G.A. / Oberholzer, A.E. / Rembeza, E. / Sorrell, F.J. / Chalk, R. / Borkowska, O. / Ellis, K. / Kupinska, K. / Krojer, T. ...

Funding support

United Kingdom, 1items

Citation

Journal: Nat Commun / Year: 2018
Title: Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition.
Authors: Froese, D.S. / Kopec, J. / Rembeza, E. / Bezerra, G.A. / Oberholzer, A.E. / Suormala, T. / Lutz, S. / Chalk, R. / Borkowska, O. / Baumgartner, M.R. / Yue, W.W.

History

Deposition	Dec 21, 2017	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	May 16, 2018	Provider: repository / Type: Initial release
Revision 1.1	Jul 4, 2018	Group: Data collection / Database references / Category: citation Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	6fcx.cif.gz	469 KB	Display	PDBx/mmCIF format
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Validation report

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

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Related structure data

Related structure data	6fnuC C: citing same article (ref.)
Similar structure data	2gm1-d 2b5t-d 7cmo-d 2wfe-d 6c45-d 3jze-d 3qxf-d 2pf4-2 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 (1)

Deposited unit

A: Methylenetetrahydrofolate reductase

B: Methylenetetrahydrofolate reductase

hetero molecules

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

1

Idetical with deposited unit
defined by author&software
Evidence: SAXS

Unit cell

Length a, b, c (Å)	97.337, 127.942, 147.015
Angle α, β, γ (deg.)	90.00, 90.00, 90.00
Int Tables number	19
Space group name H-M	P2₁2₁2₁

#1: Protein	Methylenetetrahydrofolate reductase / Mass: 70550.992 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MTHFR / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: P42898, methylenetetrahydrofolate reductase [NAD(P)H]
#2: Chemical	ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE / Flavin adenine dinucleotide Mass: 785.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₇H₃₃N₉O₁₅P₂ / Comment: FAD*YM
#3: Chemical	ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE / S-Adenosyl-L-homocysteine Type: L-peptide linking / Mass: 384.411 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₄H₂₀N₆O₅S
#4: Chemical	ChemComp-CIT / CITRIC ACID / Citric acid Mass: 192.124 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₆H₈O₇
#5: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 72 / 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: 3.24 Å³/Da / Density % sol: 62.08 %
Crystal grow	Temperature: 277.15 K / Method: vapor diffusion, sitting drop Details: 0.1M Sodium Citrate tribasic, 22.5% PEG4K, 5% 2-propanol

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Data collection

Diffraction

Mean temperature: 100 K

Diffraction source

Source:

SYNCHROTRON / Site:

Diamond

/ Beamline: I04-1 / Wavelength: 0.9281 Å

Detector

Type: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jan 14, 2017

Radiation

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

Radiation wavelength

Wavelength: 0.9281 Å / Relative weight: 1

Reflection

Resolution: 2.5→96.512 Å / Num. all: 64233 / Num. obs: 479094 / % possible obs: 100 % / Redundancy: 7.5 % / B_iso Wilson estimate: 70.51 Å² / R_pim(I) all: 0.034 / R_rim(I) all: 0.093 / R_sym value: 0.086 / Net I/av σ(I): 5 / Net I/σ(I): 12.8 / Num. measured all: 479094

Reflection shell

Diffraction-ID: 1

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Mean I/σ(I) obs	Num. unique obs	R_pim(I) all	R_rim(I) all	R_sym value	% possible all
2.5-2.64	7	1.362	0.6	9272	0.556	1.473	1.362	100
2.64-2.8	7.8	0.846	0.9	8758	0.325	0.907	0.846	100
2.8-2.99	7.7	0.441	1.7	8256	0.17	0.473	0.441	100
2.99-3.23	7.3	0.245	3.1	7681	0.097	0.264	0.245	100
3.23-3.54	7.7	0.135	5.4	7133	0.052	0.145	0.135	100
3.54-3.95	7.6	0.084	8	6449	0.032	0.09	0.084	100
3.95-4.56	7.4	0.061	9.8	5735	0.024	0.066	0.061	100
4.56-5.59	7.6	0.056	10.4	4882	0.022	0.06	0.056	100
5.59-7.91	7.2	0.055	10.2	3830	0.022	0.059	0.055	100
7.91-63.971	6.8	0.05	9.6	2237	0.021	0.054	0.05	99.7

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Processing

Software

Name	Version	Classification
PHENIX	(1.13_2998: ???)	refinement
SCALA	3.3.22	data scaling
PDB_EXTRACT	3.24	data extraction
XDS		data reduction
SHELXCD		phasing

Refinement

Method to determine structure:

MAD / Resolution: 2.5→63.971 Å / SU ML: 0.4 / Cross valid method: THROUGHOUT / σ(F): 0.09 / Phase error: 29.76 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.2475	6247	5.1 %
R_work	0.2103	-	-
obs	0.2123	122610	99.93 %

Solvent computation

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

Refinement step

Cycle: LAST / Resolution: 2.5→63.971 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	8914	0	184	72	9170

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.012	9347
X-RAY DIFFRACTION	f_angle_d	1.296	12783
X-RAY DIFFRACTION	f_dihedral_angle_d	9.941	5443
X-RAY DIFFRACTION	f_chiral_restr	0.067	1395
X-RAY DIFFRACTION	f_plane_restr	0.01	1654

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 (%)
2.5-2.5284	0.4285	221	0.359	3837	X-RAY DIFFRACTION	100
2.5284-2.5582	0.3203	197	0.3428	3937	X-RAY DIFFRACTION	100
2.5582-2.5894	0.3612	186	0.3309	3859	X-RAY DIFFRACTION	100
2.5894-2.6221	0.4005	207	0.3196	3912	X-RAY DIFFRACTION	100
2.6221-2.6566	0.3425	234	0.2967	3831	X-RAY DIFFRACTION	100
2.6566-2.693	0.3156	177	0.3009	3848	X-RAY DIFFRACTION	100
2.693-2.7315	0.4063	188	0.3019	3922	X-RAY DIFFRACTION	100
2.7315-2.7723	0.3454	222	0.2864	3924	X-RAY DIFFRACTION	100
2.7723-2.8156	0.3306	214	0.2932	3819	X-RAY DIFFRACTION	100
2.8156-2.8618	0.3191	218	0.2695	3922	X-RAY DIFFRACTION	100
2.8618-2.9111	0.3355	189	0.2724	3879	X-RAY DIFFRACTION	100
2.9111-2.964	0.2811	226	0.2589	3848	X-RAY DIFFRACTION	100
2.964-3.0211	0.3074	202	0.2592	3885	X-RAY DIFFRACTION	100
3.0211-3.0827	0.2741	209	0.2611	3895	X-RAY DIFFRACTION	100
3.0827-3.1498	0.3483	220	0.2668	3887	X-RAY DIFFRACTION	100
3.1498-3.223	0.3187	215	0.2625	3844	X-RAY DIFFRACTION	100
3.223-3.3036	0.2746	229	0.2367	3846	X-RAY DIFFRACTION	100
3.3036-3.3929	0.2918	211	0.2278	3879	X-RAY DIFFRACTION	100
3.3929-3.4928	0.2548	184	0.2316	3920	X-RAY DIFFRACTION	100
3.4928-3.6055	0.2887	255	0.2358	3869	X-RAY DIFFRACTION	100
3.6055-3.7343	0.2844	189	0.2218	3872	X-RAY DIFFRACTION	100
3.7343-3.8838	0.2427	209	0.2107	3915	X-RAY DIFFRACTION	100
3.8838-4.0606	0.2286	204	0.1928	3850	X-RAY DIFFRACTION	100
4.0606-4.2746	0.2073	213	0.1665	3880	X-RAY DIFFRACTION	100
4.2746-4.5424	0.1961	200	0.1617	3870	X-RAY DIFFRACTION	100
4.5424-4.893	0.1884	207	0.1566	3918	X-RAY DIFFRACTION	100
4.893-5.3851	0.2238	208	0.1773	3847	X-RAY DIFFRACTION	100
5.3851-6.1638	0.2347	198	0.2101	3899	X-RAY DIFFRACTION	100
6.1638-7.7636	0.2169	204	0.1984	3892	X-RAY DIFFRACTION	100
7.7636-63.9919	0.1939	211	0.175	3857	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	3.0521	0.6114	-0.4053	6.4201	-1.995	4.1663	-0.3066	0.9096	0.2098	-0.5213	0.3049	0.1419	-0.2501	0.0396	0.005	0.5073	-0.0909	-0.0366	0.8165	0.0388	0.4648	-8.8244	33.594	-31.7233
2	1.1111	0.1877	0.0415	1.5023	0.7914	2.7032	-0.1224	-0.0362	-0.2011	0.1182	0.0506	-0.0739	-0.0455	0.0611	0.0546	0.4419	0.033	0.0549	0.362	0.036	0.5213	-28.4522	18.3827	2.0035
3	1.3073	0.5158	-0.1014	6.1731	-1.6062	0.6682	0.2003	-0.6878	-0.4296	1.718	-0.064	0.142	0.0828	-0.0089	-0.0978	1.2704	-0.0533	0.0142	0.7997	0.1152	0.8165	-35.1925	-32.2574	-12.7696
4	1.1662	0.5244	1.276	2.6429	1.4925	2.6036	-0.0691	0.096	-0.0849	-0.1329	-0.239	0.5454	0.1118	-0.2117	0.2752	0.4495	-0.032	0.0447	0.4952	-0.1372	0.7056	-45.8895	-6.3561	-35.9517

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 40 through 346 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 347 through 651 )
3	X-RAY DIFFRACTION	3	chain 'B' and (resid 41 through 389 )
4	X-RAY DIFFRACTION	4	chain 'B' and (resid 390 through 648 )

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