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- PDB-8xar: Structure-Based Design and Optimization of Methionine Adenosyltra... -

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Basic information

Entry
Database: PDB / ID: 8xar
TitleStructure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with SAM and Compound 54
ComponentsS-adenosylmethionine synthase isoform type-2
KeywordsTRANSFERASE / One-carbon metabolism / Metal-binding / inhibitor complex
Function / homology
Function and homology information


methionine adenosyltransferase complex / methionine adenosyltransferase / methionine adenosyltransferase activity / S-adenosylmethionine biosynthetic process / protein heterooligomerization / Methylation / cellular response to methionine / protein hexamerization / small molecule binding / one-carbon metabolic process ...methionine adenosyltransferase complex / methionine adenosyltransferase / methionine adenosyltransferase activity / S-adenosylmethionine biosynthetic process / protein heterooligomerization / Methylation / cellular response to methionine / protein hexamerization / small molecule binding / one-carbon metabolic process / positive regulation of TORC1 signaling / cellular response to leukemia inhibitory factor / ATP binding / metal ion binding / identical protein binding / cytosol
Similarity search - Function
S-adenosylmethionine synthetase / S-adenosylmethionine synthetase, N-terminal / S-adenosylmethionine synthetase, central domain / S-adenosylmethionine synthetase, C-terminal / S-adenosylmethionine synthetase, conserved site / S-adenosylmethionine synthetase superfamily / S-adenosylmethionine synthetase, N-terminal domain / S-adenosylmethionine synthetase, central domain / S-adenosylmethionine synthetase, C-terminal domain / S-adenosylmethionine synthase signature 1. / S-adenosylmethionine synthase signature 2.
Similarity search - Domain/homology
S-ADENOSYLMETHIONINE / : / S-adenosylmethionine synthase isoform type-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.19 Å
AuthorsZheng, J.Y. / Zhang, G.P. / Li, J.J. / Tong, S.L.
Funding support China, 1items
OrganizationGrant numberCountry
Other private China
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy.
Authors: Zheng, J. / Zhang, T. / Tong, S. / Liu, T. / Cui, J. / Xu, H. / Hu, D. / Shen, Y. / Yin, Y. / Zhao, D. / Tan, C. / Dong, X. / Chen, J. / Ji, F. / Tong, C. / Li, J.J. / Li, J. / Zhang, G.
History
DepositionDec 5, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: S-adenosylmethionine synthase isoform type-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5387
Polymers45,5631
Non-polymers9756
Water9,620534
1
A: S-adenosylmethionine synthase isoform type-2
hetero molecules

A: S-adenosylmethionine synthase isoform type-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,07514
Polymers91,1252
Non-polymers1,95012
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area8110 Å2
ΔGint-44 kcal/mol
Surface area24830 Å2
Unit cell
Length a, b, c (Å)68.180, 94.160, 117.120
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-682-

HOH

21A-879-

HOH

31A-994-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein S-adenosylmethionine synthase isoform type-2


Mass: 45562.617 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAT2A / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P31153, methionine adenosyltransferase

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Non-polymers , 6 types, 540 molecules

#2: Chemical ChemComp-YMW / 7-chloranyl-2-ethyl-5-pyridin-3-yl-pyrazolo[3,4-c]quinolin-4-one


Mass: 324.764 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H13ClN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 534 / 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: 2.06 Å3/Da / Density % sol: 40.42 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1M Tris pH 8.0; 0.2M LiCl; 10% EG; 18%-22% PEG6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97935 Å
DetectorType: DECTRIS PILATUS3 X 6M / Detector: PIXEL / Date: Apr 2, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97935 Å / Relative weight: 1
ReflectionResolution: 1.19→47.12 Å / Num. obs: 117262 / % possible obs: 97.6 % / Redundancy: 13.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.022 / Rrim(I) all: 0.081 / Χ2: 0.99 / Net I/σ(I): 18.2
Reflection shellResolution: 1.19→1.21 Å / % possible obs: 89.3 % / Redundancy: 12.4 % / Rmerge(I) obs: 1.317 / Num. measured all: 65936 / Num. unique obs: 5304 / CC1/2: 0.799 / Rpim(I) all: 0.379 / Rrim(I) all: 1.371 / Χ2: 0.93 / Net I/σ(I) obs: 2.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7BHR

7bhr


Resolution: 1.19→47.12 Å / Cor.coef. Fo:Fc: 0.987 / Cor.coef. Fo:Fc free: 0.984 / SU B: 1.462 / SU ML: 0.027 / Cross valid method: THROUGHOUT / ESU R: 0.03 / ESU R Free: 0.03 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.12991 5822 5 %RANDOM
Rwork0.11103 ---
obs0.11197 111426 97.39 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 11.948 Å2
Baniso -1Baniso -2Baniso -3
1-3.3 Å20 Å2-0 Å2
2---1.23 Å2-0 Å2
3----2.06 Å2
Refinement stepCycle: 1 / Resolution: 1.19→47.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2983 0 36 534 3553
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0123430
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163275
X-RAY DIFFRACTIONr_angle_refined_deg1.4371.6754687
X-RAY DIFFRACTIONr_angle_other_deg0.4991.5927589
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8355448
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.438524
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.76910601
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0760.2507
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.024175
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02770
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_it2.0131.1251702
X-RAY DIFFRACTIONr_mcbond_other2.0131.1251702
X-RAY DIFFRACTIONr_mcangle_it3.0552.032180
X-RAY DIFFRACTIONr_mcangle_other3.0562.032181
X-RAY DIFFRACTIONr_scbond_it2.9231.3181728
X-RAY DIFFRACTIONr_scbond_other2.9221.3191729
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.3992.3362508
X-RAY DIFFRACTIONr_long_range_B_refined12.56917.244262
X-RAY DIFFRACTIONr_long_range_B_other9.63112.724010
X-RAY DIFFRACTIONr_rigid_bond_restr2.23736705
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.19→1.221 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.227 378 -
Rwork0.223 7625 -
obs--90.29 %

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