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- PDB-9g4u: Crystal structure of the human METTL3-METTL14 in complex with sma... -

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Basic information

Entry
Database: PDB / ID: 9g4u
TitleCrystal structure of the human METTL3-METTL14 in complex with small molecule inhibitor Compound 31
Components
  • N6-adenosine-methyltransferase catalytic subunit
  • N6-adenosine-methyltransferase non-catalytic subunit
KeywordsRNA BINDING PROTEIN / METTL3 METTL14 inhibitor Epics
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 methylation / regulation of meiotic cell cycle / RNA methyltransferase activity / primary miRNA processing ...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 methylation / regulation of meiotic cell cycle / RNA methyltransferase activity / primary miRNA processing / forebrain radial glial cell differentiation / oxidoreductase complex / dosage compensation by inactivation of X chromosome / S-adenosyl-L-methionine binding / gliogenesis / mRNA stabilization / mRNA modification / regulation of hematopoietic stem cell differentiation / 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 / mRNA splicing, via spliceosome / circadian rhythm / 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
: / 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
AuthorsDutheuil, G. / Oukoloff, K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Crystal structure of the human METTL3-METTL14 in complex with small molecule inhibitor Compound 31
Authors: Dutheuil, G. / Oukoloff, K.
History
DepositionJul 16, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release

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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)57,2163
Polymers56,7532
Non-polymers4641
Water4,756264
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4070 Å2
ΔGint-18 kcal/mol
Surface area20840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.082, 64.082, 225.609
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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: 24341.020 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): Sf21 / 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: 32411.834 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): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9HCE5
#3: Chemical ChemComp-A1IIK / 4-[(3~{R})-3-(cyclobutylmethylamino)piperidin-1-yl]-1-[(1~{R})-1-[4-(5-methoxypyridin-3-yl)-1,2,3-triazol-1-yl]ethyl]pyridin-2-one


Mass: 463.575 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H33N7O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 264 / 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: 2.52 Å3/Da / Density % sol: 51.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.2 M calcium chloride, 0.1 M Tris:HCl pH 8.0, 18% (w/v) PEG 4000, 20C, sitting drop, protein:precipitant solution ratio = 1:1

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97856 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 19, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2→45.12 Å / Num. obs: 35507 / % possible obs: 100 % / Redundancy: 20.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.15 / Net I/σ(I): 15.1
Reflection shellResolution: 2→2.05 Å / Num. unique obs: 2673 / CC1/2: 0.96

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Processing

Software
NameVersionClassification
REFMAC5.8.0415refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→44.69 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.948 / SU B: 4.694 / SU ML: 0.126 / Cross valid method: THROUGHOUT / ESU R: 0.174 / ESU R Free: 0.16 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23276 1896 5.1 %RANDOM
Rwork0.18736 ---
obs0.18973 35507 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 42.127 Å2
Baniso -1Baniso -2Baniso -3
1--0.49 Å2-0.25 Å2-0 Å2
2---0.49 Å20 Å2
3---1.61 Å2
Refinement stepCycle: 1 / Resolution: 2→44.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3763 0 0 264 4027
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0123862
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163640
X-RAY DIFFRACTIONr_angle_refined_deg1.431.6635239
X-RAY DIFFRACTIONr_angle_other_deg0.4621.5858386
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4285452
X-RAY DIFFRACTIONr_dihedral_angle_2_deg5.3045.28635
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.70910661
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0620.2560
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024563
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02910
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.8744.1731823
X-RAY DIFFRACTIONr_mcbond_other3.8694.1741823
X-RAY DIFFRACTIONr_mcangle_it5.6887.4642270
X-RAY DIFFRACTIONr_mcangle_other5.6877.4662271
X-RAY DIFFRACTIONr_scbond_it4.5514.6772039
X-RAY DIFFRACTIONr_scbond_other4.554.6782040
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.0828.3582968
X-RAY DIFFRACTIONr_long_range_B_refined9.69340.764332
X-RAY DIFFRACTIONr_long_range_B_other9.70840.364299
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.35 132 -
Rwork0.298 2541 -
obs--99.93 %

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