PDB-8bn8: METTL3-METTL14 heterodimer bound to the SAM competitive small mol...

ID or keywords:

Entry

Database: PDB / ID: 8bn8

Title

METTL3-METTL14 heterodimer bound to the SAM competitive small molecule inhibitor STM3006

Components

N6-adenosine-methyltransferase catalytic subunit
N6-adenosine-methyltransferase non-catalytic subunit

Keywords

RNA BINDING PROTEIN / METHYLTRANSFERASE / SAM / INHIBITOR / M6A

Function / homology

Function and homology information

negative regulation of hematopoietic progenitor cell differentiation / mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity / mRNA m6A methyltransferase / mRNA m(6)A methyltransferase activity / RNA N6-methyladenosine methyltransferase complex / positive regulation of cap-independent translational initiation / adenosine to inosine editing / RNA methyltransferase activity / endothelial to hematopoietic transition / RNA methylation ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.213 Å

Authors

Pilka, E.S. / Thomas, B. / Blackaby, W. / Hardick, D. / Feeney, K. / Ridgill, M. / Rotty, B. / Rausch, O.

Funding support

1items

Citation

Journal: Cancer Discov / Year: 2023
Title: Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity.
Authors: Guirguis, A.A. / Ofir-Rosenfeld, Y. / Knezevic, K. / Blackaby, W. / Hardick, D. / Chan, Y.C. / Motazedian, A. / Gillespie, A. / Vassiliadis, D. / Lam, E.Y.N. / Tran, K. / Andrews, B. / ...

History

Deposition	Nov 13, 2022	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Sep 20, 2023	Provider: repository / Type: Initial release
Revision 1.1	Oct 18, 2023	Group: Database references / Category: citation / citation_author Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	8bn8.cif.gz	185.5 KB	Display	PDBx/mmCIF format
PDB format	pdb8bn8.ent.gz		Display	PDB format
PDBx/mmJSON format	8bn8.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	8bn8_validation.pdf.gz	739 KB	Display	wwPDB validaton report
Full document	8bn8_full_validation.pdf.gz	746 KB	Display
Data in XML	8bn8_validation.xml.gz	19.1 KB	Display
Data in CIF	8bn8_validation.cif.gz	26.5 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/bn/8bn8 ftp://data.pdbj.org/pub/pdb/validation_reports/bn/8bn8	HTTPS FTP

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Related structure data

Related structure data	5l6dS S: Starting model for refinement
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

Deposited unit

AAA: N6-adenosine-methyltransferase catalytic subunit

BBB: N6-adenosine-methyltransferase non-catalytic subunit

hetero molecules

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

1

Idetical with deposited unit
defined by author&software
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	63.970, 63.970, 226.480
Angle α, β, γ (deg.)	90.000, 90.000, 120.000
Int Tables number	154
Space group name H-M	P3₂21

#1: Protein	N6-adenosine-methyltransferase catalytic subunit / Methyltransferase-like protein 3 / hMETTL3 / N6-adenosine-methyltransferase 70 kDa subunit / MT-A70 Mass: 25057.781 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: METTL3, MTA70 / Cell line (production host): 21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q86U44, mRNA m6A methyltransferase
#2: Protein	N6-adenosine-methyltransferase non-catalytic subunit / Methyltransferase-like protein 14 / hMETTL14 Mass: 33634.184 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: METTL14, KIAA1627 / Cell line (production host): 21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9HCE5
#3: Chemical	ChemComp-QWR / 2-[[4-(6-bromanyl-2~{H}-indazol-4-yl)-1,2,3-triazol-1-yl]methyl]-6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridine Mass: 519.439 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₅H₂₇BrN₈ / Feature type: SUBJECT OF INVESTIGATION
#4: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 83 / 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: 2.24 Å³/Da / Density % sol: 45.08 %
Crystal grow	Temperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 150 MM MAGNESIUM ACETATE, 22% W/V PEG 3350

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
Detector	Type: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 22, 2020
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.9795 Å / Relative weight: 1
Reflection	Resolution: 2.213→75.493 Å / Num. obs: 27798 / % possible obs: 100 % / Redundancy: 9.9 % / CC_1/2: 0.999 / Net I/σ(I): 12
Reflection shell	Resolution: 2.213→2.252 Å / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1337 / CC_1/2: 0.611

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0267	refinement
autoPROC		data reduction
autoPROC		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 5L6D

5l6d

Resolution: 2.213→75.493 Å / Cor.coef. F_o:F_c: 0.962 / Cor.coef. F_o:F_c free: 0.935 / SU B: 13.743 / SU ML: 0.159 / Cross valid method: THROUGHOUT / ESU R: 0.237 / ESU R Free: 0.207
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2442	1377	4.954 %
R_work	0.1842	26420	-
all	0.187	-	-
obs	-	27797	99.91 %

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: 47.357 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.126 Å²	-0.063 Å²	-0 Å²
2-	-	-0.126 Å²	0 Å²
3-	-	-	0.41 Å²

Refinement step

Cycle: LAST / Resolution: 2.213→75.493 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	3608	0	34	83	3725

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.013	0.013	3752
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.015	3523
X-RAY DIFFRACTION	r_angle_refined_deg	1.945	1.659	5098
X-RAY DIFFRACTION	r_angle_other_deg	1.356	1.593	8111
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	8.2	5	438
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	35.215	21.606	218
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	16.766	15	635
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	19.636	15	31
X-RAY DIFFRACTION	r_chiral_restr	0.081	0.2	475
X-RAY DIFFRACTION	r_gen_planes_refined	0.01	0.02	4215
X-RAY DIFFRACTION	r_gen_planes_other	0.002	0.02	899
X-RAY DIFFRACTION	r_nbd_refined	0.218	0.2	749
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.195	0.2	3508
X-RAY DIFFRACTION	r_nbtor_refined	0.176	0.2	1801
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.084	0.2	1884
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.149	0.2	128
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.121	0.2	1
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.174	0.2	3
X-RAY DIFFRACTION	r_nbd_other	0.179	0.2	43
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.077	0.2	5
X-RAY DIFFRACTION	r_mcbond_it	3.154	4.298	1761
X-RAY DIFFRACTION	r_mcbond_other	3.149	4.297	1760
X-RAY DIFFRACTION	r_mcangle_it	4.835	6.415	2190
X-RAY DIFFRACTION	r_mcangle_other	4.837	6.418	2191
X-RAY DIFFRACTION	r_scbond_it	3.609	4.711	1991
X-RAY DIFFRACTION	r_scbond_other	3.608	4.713	1992
X-RAY DIFFRACTION	r_scangle_it	5.613	6.913	2906
X-RAY DIFFRACTION	r_scangle_other	5.612	6.915	2907
X-RAY DIFFRACTION	r_lrange_it	7.899	49.127	4172
X-RAY DIFFRACTION	r_lrange_other	7.901	49.107	4167

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
2.213-2.271	0.329	82	0.268	1913	0.27	2001	0.804	0.832	99.7001	0.262
2.271-2.333	0.349	89	0.252	1866	0.256	1955	0.782	0.847	100	0.243
2.333-2.401	0.293	93	0.236	1812	0.239	1906	0.869	0.879	99.9475	0.225
2.401-2.474	0.317	84	0.23	1791	0.234	1875	0.854	0.894	100	0.214
2.474-2.555	0.283	79	0.209	1726	0.212	1808	0.9	0.915	99.8341	0.191
2.555-2.645	0.282	88	0.203	1671	0.207	1759	0.898	0.922	100	0.182
2.645-2.745	0.26	77	0.197	1595	0.2	1672	0.916	0.931	100	0.172
2.745-2.857	0.242	91	0.198	1539	0.2	1630	0.921	0.931	100	0.17
2.857-2.983	0.304	74	0.201	1476	0.205	1550	0.88	0.931	100	0.175
2.983-3.129	0.247	93	0.203	1417	0.206	1510	0.923	0.926	100	0.179
3.129-3.298	0.278	63	0.207	1383	0.211	1446	0.913	0.919	100	0.184
3.298-3.497	0.236	88	0.18	1271	0.184	1359	0.932	0.948	100	0.165
3.497-3.738	0.259	84	0.175	1210	0.181	1294	0.921	0.951	100	0.163
3.738-4.037	0.206	61	0.162	1150	0.164	1211	0.955	0.964	100	0.154
4.037-4.421	0.199	35	0.136	1069	0.138	1104	0.97	0.975	100	0.134
4.421-4.941	0.177	58	0.13	958	0.132	1022	0.97	0.978	99.4129	0.132
4.941-5.701	0.232	57	0.151	849	0.155	906	0.962	0.978	100	0.15
5.701-6.972	0.258	29	0.169	760	0.172	789	0.956	0.97	100	0.167
6.972-9.819	0.262	30	0.184	594	0.188	624	0.936	0.955	100	0.2
9.819-75.493	0.198	22	0.252	370	0.249	394	0.958	0.947	99.4924	0.289

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	0.2215	0.0154	-0.084	0.8577	0.4281	0.614	0.0094	-0.0354	0.0358	-0.0056	-0.0328	0.0815	-0.0255	-0.0203	0.0234	0.0351	-0.0058	0.0162	0.0282	-0.0149	0.0208	-35.3578	28.6848	28.3949
2	0.0458	0.1221	-0.0099	0.5116	0.3445	0.748	-0.0069	0.0068	0.0039	-0.0266	0.0071	0.0102	0.0009	-0.0392	-0.0002	0.0627	-0.0361	0.0073	0.0349	-0.002	0.0016	-32.8098	8.352	3.4944

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	ALL	AAA	368 - 574
2	X-RAY DIFFRACTION	2	ALL	BBB	118 - 394

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