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- PDB-7o2f: Crystal structure of the human METTL3-METTL14 complex bound to Co... -

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Basic information

Entry
Database: PDB / ID: 7o2f
TitleCrystal structure of the human METTL3-METTL14 complex bound to Compound 22 (UZH2)
Components
  • N6-adenosine-methyltransferase catalytic subunit
  • N6-adenosine-methyltransferase non-catalytic subunit
KeywordsTRANSFERASE / METTL3 / Inhibitor / complex
Function / homology
Function and homology information


negative regulation of hematopoietic progenitor cell differentiation / positive regulation of cap-independent translational initiation / mRNA m6A methyltransferase / mRNA m(6)A methyltransferase activity / RNA N6-methyladenosine methyltransferase complex / RNA methylation / endothelial to hematopoietic transition / regulation of meiotic cell cycle / RNA methyltransferase activity / primary miRNA processing ...negative regulation of hematopoietic progenitor cell differentiation / positive regulation of cap-independent translational initiation / mRNA m6A methyltransferase / mRNA m(6)A methyltransferase activity / RNA N6-methyladenosine methyltransferase complex / RNA methylation / endothelial to hematopoietic transition / regulation of meiotic cell cycle / RNA methyltransferase activity / primary miRNA processing / forebrain radial glial cell differentiation / dosage compensation by inactivation of X chromosome / oxidoreductase complex / S-adenosyl-L-methionine binding / gliogenesis / mRNA stabilization / regulation of hematopoietic stem cell differentiation / mRNA modification / regulation of neuron differentiation / regulation of T cell differentiation / negative regulation of type I interferon-mediated signaling pathway / oogenesis / stem cell population maintenance / mRNA destabilization / Processing of Capped Intron-Containing Pre-mRNA / negative regulation of Notch signaling pathway / positive regulation of translation / response to nutrient levels / circadian rhythm / mRNA splicing, via spliceosome / mRNA processing / cellular response to UV / spermatogenesis / nuclear speck / nuclear body / 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
ACETATE ION / Chem-UZ5 / N(6)-adenosine-methyltransferase catalytic subunit METTL3 / N(6)-adenosine-methyltransferase non-catalytic subunit METTL14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsBedi, R.K. / Dolbois, A. / Caflisch, A.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation310030B_189363 Switzerland
CitationJournal: J.Med.Chem. / Year: 2021
Title: 1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors.
Authors: Dolbois, A. / Bedi, R.K. / Bochenkova, E. / Muller, A. / Moroz-Omori, E.V. / Huang, D. / Caflisch, A.
History
DepositionMar 30, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 1, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 15, 2021Group: Database references / Category: citation / citation_author / Item: _citation.title
Revision 1.2Sep 22, 2021Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)62,3384
Polymers61,7652
Non-polymers5732
Water3,909217
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4150 Å2
ΔGint-22 kcal/mol
Surface area18810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.250, 64.250, 225.770
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z

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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: 28144.080 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: METTL3, MTA70 / 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: 33621.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: METTL14, KIAA1627 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9HCE5
#3: Chemical ChemComp-UZ5 / 4-[4-[(4,4-dimethylpiperidin-1-yl)methyl]-2,5-bis(fluoranyl)phenyl]-9-[6-(methylamino)pyrimidin-4-yl]-1,4,9-triazaspiro[5.5]undecan-2-one


Mass: 513.626 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H37F2N7O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.18 Å3/Da / Density % sol: 43.52 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: 20% PEG 3350, 400mM Mg acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Feb 24, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→44.74 Å / Num. obs: 32606 / % possible obs: 99.3 % / Redundancy: 6.56 % / Biso Wilson estimate: 37.04 Å2 / CC1/2: 0.998 / Net I/σ(I): 12.77
Reflection shellResolution: 2.1→2.22 Å / Num. unique obs: 5099 / CC1/2: 0.614

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.19.1_4122refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7ACD

7acd


Resolution: 2.1→44.74 Å / SU ML: 0.2601 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.9203
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2421 1627 5 %
Rwork0.1971 30942 -
obs0.1994 32569 99.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.33 Å2
Refinement stepCycle: LAST / Resolution: 2.1→44.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3464 0 41 217 3722
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00763599
X-RAY DIFFRACTIONf_angle_d0.96324907
X-RAY DIFFRACTIONf_chiral_restr0.0538529
X-RAY DIFFRACTIONf_plane_restr0.0089632
X-RAY DIFFRACTIONf_dihedral_angle_d13.4206498
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.160.32521280.28132454X-RAY DIFFRACTION96.99
2.16-2.230.28991340.25862540X-RAY DIFFRACTION99.18
2.23-2.310.31341330.2462519X-RAY DIFFRACTION99.77
2.31-2.40.29531340.23652544X-RAY DIFFRACTION99.74
2.4-2.510.26741330.21662527X-RAY DIFFRACTION100
2.51-2.640.28941360.21312585X-RAY DIFFRACTION99.93
2.64-2.810.27881360.21442584X-RAY DIFFRACTION99.93
2.81-3.020.27651350.22832563X-RAY DIFFRACTION99.96
3.02-3.330.2871340.20872574X-RAY DIFFRACTION99.3
3.33-3.810.1821370.17622617X-RAY DIFFRACTION99.67
3.81-4.80.1691390.15252641X-RAY DIFFRACTION99.71
4.8-44.740.25241480.19022794X-RAY DIFFRACTION99.29

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