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- PDB-6ttx: Crystal structure of the human METTL3-METTL14 complex bound to Co... -

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Basic information

Entry
Database: PDB / ID: 6ttx
TitleCrystal structure of the human METTL3-METTL14 complex bound to Compound 5 (ASI_M3M_051)
Components
  • N6-adenosine-methyltransferase catalytic subunit
  • N6-adenosine-methyltransferase non-catalytic subunit
KeywordsTRANSFERASE / Compound / Complex / Mettl3 / Mettl14 / Epitranscriptomic
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-NX8 / 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 Å
AuthorsBedi, R.K. / Huang, D. / Sledz, P. / Caflisch, A.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation310030B_189363 Switzerland
CitationJournal: Chemmedchem / Year: 2020
Title: Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer.
Authors: Bedi, R.K. / Huang, D. / Eberle, S.A. / Wiedmer, L. / Sledz, P. / Caflisch, A.
History
DepositionDec 30, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 16, 2020Group: Database references / Category: citation / citation_author
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
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 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

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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)117,2294
Polymers116,7922
Non-polymers4362
Water5,765320
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4100 Å2
ΔGint-23 kcal/mol
Surface area18480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.210, 64.210, 226.380
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: 64562.879 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: 52229.449 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-NX8 / (2~{S},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)-~{N}-(piperidin-4-ylmethyl)oxolane-2-carboxamide


Mass: 377.398 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H23N7O4 / 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.: 320 / 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

Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: 25% PEG 3350, 200 mM Magnesium 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: Jun 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→45.27 Å / Num. obs: 37538 / % possible obs: 99.8 % / Redundancy: 6.5 % / Biso Wilson estimate: 32.36 Å2 / CC1/2: 0.999 / Net I/σ(I): 13.35
Reflection shellResolution: 2→2.12 Å / Num. unique obs: 5913 / CC1/2: 0.674

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.17.1_3660refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5L6D

5l6d


Resolution: 2→44.77 Å / SU ML: 0.2495 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.6253
RfactorNum. reflection% reflection
Rfree0.2173 1872 5.01 %
Rwork0.1914 --
obs0.1927 37380 99.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 36.87 Å2
Refinement stepCycle: LAST / Resolution: 2→44.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3398 0 31 320 3749
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00863540
X-RAY DIFFRACTIONf_angle_d0.94884819
X-RAY DIFFRACTIONf_chiral_restr0.0572529
X-RAY DIFFRACTIONf_plane_restr0.0067616
X-RAY DIFFRACTIONf_dihedral_angle_d19.1669470
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.060.34131400.2882650X-RAY DIFFRACTION98.9
2.06-2.120.31171400.29022660X-RAY DIFFRACTION99.08
2.12-2.190.2991410.24952672X-RAY DIFFRACTION99.65
2.19-2.260.32941430.26032711X-RAY DIFFRACTION99.24
2.26-2.350.28341420.21772685X-RAY DIFFRACTION99.72
2.35-2.460.28421430.21172722X-RAY DIFFRACTION99.93
2.46-2.590.20991420.20272689X-RAY DIFFRACTION99.82
2.59-2.750.25881420.20172707X-RAY DIFFRACTION99.82
2.75-2.970.21591450.19482737X-RAY DIFFRACTION99.86
2.97-3.260.21991450.18992764X-RAY DIFFRACTION99.86
3.27-3.740.18361450.16012753X-RAY DIFFRACTION99.69
3.74-4.710.16411470.1462800X-RAY DIFFRACTION99.56
4.71-44.770.19411570.19162958X-RAY DIFFRACTION99.46

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