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- PDB-8p1t: Crystal structure of human methionine adenosyltransferase 2A (MAT... -

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Basic information

Entry
Database: PDB / ID: 8p1t
TitleCrystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor Z237451470
ComponentsS-adenosylmethionine synthase isoform type-2
KeywordsTRANSFERASE / METHIONINE ADENOSYLTRANSFERASE / S-ADENOSYLMETHIONINE SYNTHASE ISOFORM 2 TYPE-2 / SAM / ALLOSTERIC INHIBITOR
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 / Chem-WJL / S-adenosylmethionine synthase isoform type-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.442 Å
AuthorsThomsen, M. / Thieulin-Pardo, G. / Neumann, L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2023
Title: Discovery of novel methionine adenosyltransferase 2A (MAT2A) allosteric inhibitors by structure-based virtual screening.
Authors: Kalliokoski, T. / Kettunen, H. / Kumpulainen, E. / Kettunen, E. / Thieulin-Pardo, G. / Neumann, L. / Thomsen, M. / Paul, R. / Malyutina, A. / Georgiadou, M.
History
DepositionMay 12, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 30, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)46,89311
Polymers45,7041
Non-polymers1,19010
Water7,476415
1
AAA: S-adenosylmethionine synthase isoform type-2
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)93,78722
Polymers91,4072
Non-polymers2,37920
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area9770 Å2
ΔGint-37 kcal/mol
Surface area24580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.858, 93.482, 116.793
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11AAA-615-

HOH

21AAA-628-

HOH

31AAA-818-

HOH

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Components

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Protein , 1 types, 1 molecules AAA

#1: Protein S-adenosylmethionine synthase isoform type-2 / AdoMet synthase 2 / Methionine adenosyltransferase 2 / MAT 2 / Methionine adenosyltransferase II / MAT-II


Mass: 45703.684 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAT2A, AMS2, MATA2 / Production host: Escherichia coli (E. coli) / References: UniProt: P31153, methionine adenosyltransferase

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Non-polymers , 6 types, 425 molecules

#2: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#3: Chemical ChemComp-WJL / 6-cyclopropyl-~{N}-(1~{H}-indazol-5-yl)-1-propan-2-yl-pyrazolo[3,4-b]pyridine-4-carboxamide


Mass: 360.412 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20N6O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 415 / 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: 2.03 Å3/Da / Density % sol: 39.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.10 M HEPES pH 8.0, 8 - 12%(v/v) Ethylene glycol, 8 - 10.0% (w/v) PEG8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1.1807 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 21, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1807 Å / Relative weight: 1
ReflectionResolution: 1.44→54.98 Å / Num. obs: 67105 / % possible obs: 100 % / Redundancy: 8 % / CC1/2: 0.99 / Rmerge(I) obs: 0.097 / Rpim(I) all: 0.034 / Rsym value: 0.09 / Net I/σ(I): 14.1
Reflection shellResolution: 1.44→1.47 Å / Rmerge(I) obs: 1.616 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 3302 / CC1/2: 0.614 / Rpim(I) all: 0.568 / Rsym value: 1.511

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.442→54.976 Å / Cor.coef. Fo:Fc: 0.985 / Cor.coef. Fo:Fc free: 0.978 / WRfactor Rfree: 0.138 / WRfactor Rwork: 0.108 / SU B: 2.53 / SU ML: 0.04 / Average fsc free: 0.9359 / Average fsc work: 0.9423 / Cross valid method: FREE R-VALUE / ESU R: 0.061 / ESU R Free: 0.054
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1513 4755 7.086 %
Rwork0.1175 62345 -
all0.12 --
obs-67100 99.982 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 16.737 Å2
Baniso -1Baniso -2Baniso -3
1-1.141 Å20 Å2-0 Å2
2---0.342 Å20 Å2
3----0.799 Å2
Refinement stepCycle: LAST / Resolution: 1.442→54.976 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2972 0 80 415 3467
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0133308
X-RAY DIFFRACTIONr_bond_other_d0.0090.0173121
X-RAY DIFFRACTIONr_angle_refined_deg1.4041.6624517
X-RAY DIFFRACTIONr_angle_other_deg1.4681.5937207
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8595431
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.79921.914162
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.28315.027547
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg50.756202
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6411522
X-RAY DIFFRACTIONr_dihedral_angle_6_deg11202
X-RAY DIFFRACTIONr_chiral_restr0.0790.2424
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023871
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02735
X-RAY DIFFRACTIONr_nbd_refined0.210.2689
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1810.23006
X-RAY DIFFRACTIONr_nbtor_refined0.1610.21565
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0730.21385
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1250.2357
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0650.21
X-RAY DIFFRACTIONr_metal_ion_refined0.1430.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1550.228
X-RAY DIFFRACTIONr_nbd_other0.160.2137
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1970.259
X-RAY DIFFRACTIONr_mcbond_it1.1031.521658
X-RAY DIFFRACTIONr_mcbond_other1.1031.5211658
X-RAY DIFFRACTIONr_mcangle_it1.3912.2942111
X-RAY DIFFRACTIONr_mcangle_other1.3912.2942112
X-RAY DIFFRACTIONr_scbond_it1.531.7781650
X-RAY DIFFRACTIONr_scbond_other1.5291.7791651
X-RAY DIFFRACTIONr_scangle_it1.882.5642403
X-RAY DIFFRACTIONr_scangle_other1.882.5652404
X-RAY DIFFRACTIONr_lrange_it3.07820.2913892
X-RAY DIFFRACTIONr_lrange_other2.48719.2463767
X-RAY DIFFRACTIONr_rigid_bond_restr1.98336425
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.442-1.4790.2943270.2754545X-RAY DIFFRACTION99.959
1.479-1.520.2543460.2294460X-RAY DIFFRACTION99.9584
1.52-1.5640.2333370.2014300X-RAY DIFFRACTION99.9784
1.564-1.6120.1972990.1714249X-RAY DIFFRACTION100
1.612-1.6650.193020.1434070X-RAY DIFFRACTION99.9771
1.665-1.7230.1593090.1253947X-RAY DIFFRACTION100
1.723-1.7880.1663130.1173814X-RAY DIFFRACTION100
1.788-1.8610.1662800.1033659X-RAY DIFFRACTION100
1.861-1.9440.1342670.0913552X-RAY DIFFRACTION100
1.944-2.0380.1262560.0863363X-RAY DIFFRACTION100
2.038-2.1490.1412480.0883213X-RAY DIFFRACTION100
2.149-2.2790.1262540.0823037X-RAY DIFFRACTION99.9696
2.279-2.4360.1232250.0832865X-RAY DIFFRACTION100
2.436-2.6310.1442030.0942687X-RAY DIFFRACTION99.9654
2.631-2.8820.1291890.0952471X-RAY DIFFRACTION100
2.882-3.2210.1271730.1042244X-RAY DIFFRACTION100
3.221-3.7180.1471310.1182035X-RAY DIFFRACTION99.9539
3.718-4.5510.1341180.111715X-RAY DIFFRACTION100
4.551-6.4230.161140.1421329X-RAY DIFFRACTION100
6.423-54.9760.15640.163790X-RAY DIFFRACTION99.6499

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