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- PDB-7o2i: METTL3-METTL14 heterodimer bound to the SAM competitive small mol... -

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Basic information

Entry
Database: PDB / ID: 7o2i
TitleMETTL3-METTL14 heterodimer bound to the SAM competitive small molecule inhibitor STM2457
Components
  • N6-adenosine-methyltransferase catalytic subunit
  • N6-adenosine-methyltransferase non-catalytic subunit
KeywordsRNA BINDING PROTEIN / methyltransferase / SAM / inhibitor / m6A
Function / homology
Function and homology information


mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity / mRNA m6A methyltransferase / RNA N6-methyladenosine methyltransferase complex / negative regulation of hematopoietic progenitor cell differentiation / mRNA m(6)A methyltransferase activity / positive regulation of cap-independent translational initiation / adenosine to inosine editing / endothelial to hematopoietic transition / RNA methyltransferase activity / regulation of meiotic cell cycle ...mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity / mRNA m6A methyltransferase / RNA N6-methyladenosine methyltransferase complex / negative regulation of hematopoietic progenitor cell differentiation / mRNA m(6)A methyltransferase activity / positive regulation of cap-independent translational initiation / adenosine to inosine editing / endothelial to hematopoietic transition / RNA methyltransferase activity / regulation of meiotic cell cycle / primary miRNA processing / : / RNA methylation / forebrain radial glial cell differentiation / gliogenesis / dosage compensation by inactivation of X chromosome / S-adenosyl-L-methionine binding / regulation of hematopoietic stem cell differentiation / regulation of T cell differentiation / regulation of neuron differentiation / negative regulation of type I interferon-mediated signaling pathway / oogenesis / stem cell population maintenance / mRNA destabilization / negative regulation of Notch signaling pathway / mRNA catabolic process / Processing of Capped Intron-Containing Pre-mRNA / positive regulation of translation / mRNA splicing, via spliceosome / mRNA processing / circadian rhythm / cellular response to UV / spermatogenesis / nuclear body / nuclear speck / protein heterodimerization activity / innate immune response / mRNA binding / DNA damage response / Golgi apparatus / nucleoplasm / nucleus / cytosol
Similarity search - Function
N6-adenosine-methyltransferase non-catalytic subunit METTL14-like / mRNA (2'-O-methyladenosine-N(6)-)-methyltransferase-like (MT-A70-like) family profile. / N6-adenosine-methyltransferase MT-A70-like / mRNA (2'-O-methyladenosine-N(6)-)-methyltransferase (EC 2.1.1.62) family profile. / MT-A70-like / MT-A70 / MT-A70-like family profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
Chem-V22 / N6-adenosine-methyltransferase catalytic subunit / N6-adenosine-methyltransferase non-catalytic subunit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsPilka, E.S. / Blackaby, W. / Hardick, D. / Harper, C. / Hewstone, D. / Ridgill, M. / Rotty, B. / Rausch, O.
CitationJournal: Nature / Year: 2021
Title: Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.
Authors: Yankova, E. / Blackaby, W. / Albertella, M. / Rak, J. / De Braekeleer, E. / Tsagkogeorga, G. / Pilka, E.S. / Aspris, D. / Leggate, D. / Hendrick, A.G. / Webster, N.A. / Andrews, B. / ...Authors: Yankova, E. / Blackaby, W. / Albertella, M. / Rak, J. / De Braekeleer, E. / Tsagkogeorga, G. / Pilka, E.S. / Aspris, D. / Leggate, D. / Hendrick, A.G. / Webster, N.A. / Andrews, B. / Fosbeary, R. / Guest, P. / Irigoyen, N. / Eleftheriou, M. / Gozdecka, M. / Dias, J.M.L. / Bannister, A.J. / Vick, B. / Jeremias, I. / Vassiliou, G.S. / Rausch, O. / Tzelepis, K. / Kouzarides, T.
History
DepositionMar 30, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 9, 2021Group: 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
Revision 1.3Jan 31, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: N6-adenosine-methyltransferase catalytic subunit
B: N6-adenosine-methyltransferase non-catalytic subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,1764
Polymers59,6522
Non-polymers5242
Water41423
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5290 Å2
ΔGint-15 kcal/mol
Surface area19360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.094, 64.094, 225.302
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein N6-adenosine-methyltransferase catalytic subunit / Methyltransferase-like protein 3 / hMETTL3 / N6-adenosine-methyltransferase 70 kDa subunit / MT-A70


Mass: 26017.844 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-V22 / ~{N}-[[6-[(cyclohexylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxidanylidene-1~{H}-pyrido[1,2-a]pyrimidine-2-carboxamide


Mass: 445.537 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H29N6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 23 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.24 Å3/Da / Density % sol: 45.08 %
Crystal growTemperature: 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

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 18, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 3→49.795 Å / Num. obs: 11480 / % possible obs: 100 % / Redundancy: 19.7 % / CC1/2: 0.996 / Rrim(I) all: 0.274 / Net I/σ(I): 12.2
Reflection shellResolution: 3→3.18 Å / Redundancy: 15 % / Rmerge(I) obs: 1.8 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 1804 / CC1/2: 0.697 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5L6D

5l6d


Resolution: 3→49.795 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.89 / SU B: 41.69 / SU ML: 0.349 / Cross valid method: THROUGHOUT / ESU R Free: 0.462
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2626 508 4.444 %
Rwork0.1859 10924 -
all0.189 --
obs-11432 99.956 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 60.364 Å2
Baniso -1Baniso -2Baniso -3
1--1.463 Å2-0.731 Å2-0 Å2
2---1.463 Å20 Å2
3---4.745 Å2
Refinement stepCycle: LAST / Resolution: 3→49.795 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3580 0 37 23 3640
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0133712
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173415
X-RAY DIFFRACTIONr_angle_refined_deg1.2871.6585034
X-RAY DIFFRACTIONr_angle_other_deg1.1351.597917
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.6735431
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.74121.759216
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.60515626
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4131530
X-RAY DIFFRACTIONr_chiral_restr0.0550.2466
X-RAY DIFFRACTIONr_gen_planes_refined0.010.024133
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02823
X-RAY DIFFRACTIONr_nbd_refined0.2350.2886
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2250.23570
X-RAY DIFFRACTIONr_nbtor_refined0.1780.21749
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0830.21805
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1810.2109
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0580.23
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1150.29
X-RAY DIFFRACTIONr_nbd_other0.2160.234
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1130.22
X-RAY DIFFRACTIONr_mcbond_it3.1175.1121745
X-RAY DIFFRACTIONr_mcbond_other3.1045.111744
X-RAY DIFFRACTIONr_mcangle_it5.2027.6482169
X-RAY DIFFRACTIONr_mcangle_other5.2027.6512170
X-RAY DIFFRACTIONr_scbond_it3.0375.481967
X-RAY DIFFRACTIONr_scbond_other3.0375.481968
X-RAY DIFFRACTIONr_scangle_it4.998.1022865
X-RAY DIFFRACTIONr_scangle_other4.998.1032866
X-RAY DIFFRACTIONr_lrange_it8.1759.2654263
X-RAY DIFFRACTIONr_lrange_other8.16959.274264
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
3-3.0780.349350.2587920.2618280.7640.82199.87920.222
3.078-3.1620.304210.2547770.2557980.8250.8411000.221
3.162-3.2530.225390.2287340.2287730.8810.8851000.195
3.253-3.3530.384330.2057220.217550.7970.9061000.166
3.353-3.4620.253360.1877020.197380.9190.9321000.159
3.462-3.5830.203330.1776940.1787270.9340.941000.149
3.583-3.7180.283540.1726260.186800.9050.9431000.15
3.718-3.8680.276300.1766320.1816620.9070.9421000.149
3.868-4.0390.184300.1646240.1656540.9420.9521000.148
4.039-4.2350.285220.1575800.1616020.90.9551000.141
4.235-4.4620.195240.1555670.1575910.9520.961000.141
4.462-4.7310.241260.145340.1445600.9360.9671000.128
4.731-5.0540.266370.1774920.1835290.9190.9521000.157
5.054-5.4540.312160.2034800.2084960.9420.941000.182
5.454-5.9680.17480.2084520.2074600.9020.941000.183
5.968-6.660.414240.2013930.2124170.9140.9451000.18
6.66-7.6680.329170.2013660.2063830.9210.9461000.181
7.668-9.3360.25990.1673300.1693390.9220.971000.162
9.336-12.9770.12860.1682590.1672650.9850.9751000.17
12.977-49.7950.28580.2921680.2921760.9360.941000.273
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°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)
10.34450.1203-0.171.69340.76831.3485-0.04610.01080.03470.1266-0.0120.0575-0.0242-0.05890.0580.0872-0.01720.0220.0134-0.010.1203-35.138428.810728.3691
20.01810.11860.08481.16570.6571.4169-0.02720.0203-0.01370.03850.0589-0.04570.0207-0.0941-0.03170.0995-0.06360.02030.0646-0.01770.1619-32.7128.68553.7264
Refinement TLS group
IDRefine-IDRefine TLS-IDSelectionAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1ALLA368 - 572
2X-RAY DIFFRACTION2ALLB117 - 401

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