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- PDB-7ni7: Crystal structure of the human METTL3-METTL14 complex with compou... -

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Basic information

Entry
Database: PDB / ID: 7ni7
TitleCrystal structure of the human METTL3-METTL14 complex with compound UOZ031
Components(N6-adenosine-methyltransferase ...) x 2
KeywordsTRANSFERASE / METTL3 / METTL14 / M6A / Inhibitor / Complex
Function / homology
Function and homology information


negative regulation of hematopoietic progenitor cell differentiation / mRNA m6A methyltransferase / mRNA m(6)A methyltransferase activity / RNA N6-methyladenosine methyltransferase complex / positive regulation of cap-independent translational initiation / endothelial to hematopoietic transition / RNA methyltransferase activity / regulation of meiotic cell cycle / RNA methylation / dosage compensation by inactivation of X chromosome ...negative regulation of hematopoietic progenitor cell differentiation / mRNA m6A methyltransferase / mRNA m(6)A methyltransferase activity / RNA N6-methyladenosine methyltransferase complex / positive regulation of cap-independent translational initiation / endothelial to hematopoietic transition / RNA methyltransferase activity / regulation of meiotic cell cycle / RNA methylation / dosage compensation by inactivation of X chromosome / primary miRNA processing / forebrain radial glial cell differentiation / oxidoreductase complex / S-adenosyl-L-methionine binding / regulation of hematopoietic stem cell differentiation / mRNA stabilization / gliogenesis / mRNA modification / regulation of neuron differentiation / regulation of T cell differentiation / negative regulation of type I interferon-mediated signaling pathway / stem cell population maintenance / oogenesis / 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
ACETATE ION / Chem-UEH / 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: 2.5 Å
AuthorsBedi, R.K. / Huang, D. / Caflisch, A.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation310030B_189363 Switzerland
CitationJournal: Acs Bio Med Chem Au / Year: 2023
Title: Structure-Based Design of Inhibitors of the m6A-RNA Writer Enzyme METTL3
Authors: Bedi, R.K. / Huang, D. / Li, Y. / Caflisch, A.
History
DepositionFeb 11, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 20, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 21, 2023Group: 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.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)62,4645
Polymers61,7652
Non-polymers6993
Water1,35175
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4260 Å2
ΔGint-30 kcal/mol
Surface area18980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.140, 64.140, 225.970
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
Components on special symmetry positions
IDModelComponents
11B-548-

HOH

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Components

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N6-adenosine-methyltransferase ... , 2 types, 2 molecules AB

#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

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Non-polymers , 4 types, 78 molecules

#3: Chemical ChemComp-UEH / (R)-4-((4,4-dimethylpiperidin-1-yl)methyl)-2-hydroxy-N-((3-hydroxy-1-(6-((3-(methylcarbamoyl)benzyl)amino)pyrimidin-4-yl)piperidin-3-yl)methyl)benzamide / 4-[(4,4-dimethylpiperidin-1-yl)methyl]-~{N}-[[(3~{R})-1-[6-[[3-(methylcarbamoyl)phenyl]methylamino]pyrimidin-4-yl]-3-oxidanyl-piperidin-3-yl]methyl]-2-oxidanyl-benzamide


Mass: 615.766 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H45N7O4
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 75 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.17 Å3/Da / Density % sol: 43.38 %
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: Dec 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→45.2 Å / Num. obs: 19556 / % possible obs: 99.7 % / Redundancy: 9.5 % / Biso Wilson estimate: 49.71 Å2 / CC1/2: 0.993 / Net I/σ(I): 7.99
Reflection shellResolution: 2.5→2.65 Å / Num. unique obs: 3053 / CC1/2: 0.458

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.19.1_4122refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5L6D

5l6d


Resolution: 2.5→39.61 Å / SU ML: 0.3718 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.4773
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2837 972 5 %
Rwork0.2081 18487 -
obs0.2118 19459 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 47.25 Å2
Refinement stepCycle: LAST / Resolution: 2.5→39.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3460 0 46 75 3581
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00833597
X-RAY DIFFRACTIONf_angle_d1.03494904
X-RAY DIFFRACTIONf_chiral_restr0.0574533
X-RAY DIFFRACTIONf_plane_restr0.0079632
X-RAY DIFFRACTIONf_dihedral_angle_d13.97492
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.630.34931340.28192540X-RAY DIFFRACTION98.6
2.63-2.80.33761370.28432617X-RAY DIFFRACTION99.82
2.8-3.010.34151350.26112576X-RAY DIFFRACTION99.85
3.01-3.310.30461380.22812615X-RAY DIFFRACTION99.82
3.32-3.790.28211390.20052649X-RAY DIFFRACTION99.93
3.79-4.780.23981400.16852655X-RAY DIFFRACTION99.68
4.78-39.610.2761490.19642835X-RAY DIFFRACTION99.5

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