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- PDB-8p1v: Crystal structure of human methionine adenosyltransferase 2A (MAT... -

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Basic information

Entry
Database: PDB / ID: 8p1v
TitleCrystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric compound 2
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-WIV / S-adenosylmethionine synthase isoform type-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.54 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)46,86711
Polymers45,7041
Non-polymers1,16310
Water7,062392
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)93,73322
Polymers91,4072
Non-polymers2,32620
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area9780 Å2
ΔGint-93 kcal/mol
Surface area24620 Å2
Unit cell
Length a, b, c (Å)67.935, 93.812, 116.773
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-551-

HOH

21AAA-608-

HOH

31AAA-781-

HOH

41AAA-881-

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 , 5 types, 402 molecules

#2: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


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


Mass: 374.439 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22N6O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 392 / 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: 2.04 Å3/Da / Density % sol: 39.57 %
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: 1.54→73.13 Å / Num. obs: 55294 / % possible obs: 99.7 % / Redundancy: 7.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.092 / Rpim(I) all: 0.033 / Rsym value: 0.085 / Net I/σ(I): 14.4
Reflection shellResolution: 1.54→1.57 Å / Rmerge(I) obs: 1.247 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 2721 / CC1/2: 0.651 / Rpim(I) all: 0.437 / Rsym value: 1.1651

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
autoPROCdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.54→73.13 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.948 / SU B: 4.765 / SU ML: 0.072 / Cross valid method: FREE R-VALUE / ESU R: 0.11 / ESU R Free: 0.086
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2065 3914 7.182 %
Rwork0.1624 50587 -
all0.166 --
obs-54501 98.271 %
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: 18.651 Å2
Baniso -1Baniso -2Baniso -3
1-2.913 Å2-0 Å2-0 Å2
2---0.854 Å2-0 Å2
3----2.059 Å2
Refinement stepCycle: LAST / Resolution: 1.54→73.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2972 0 75 392 3439
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0133168
X-RAY DIFFRACTIONr_bond_other_d0.0090.0172999
X-RAY DIFFRACTIONr_angle_refined_deg1.371.664304
X-RAY DIFFRACTIONr_angle_other_deg1.3721.5946917
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9795401
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.6822.215158
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.29315.028531
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg51.259202
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4541520
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.849202
X-RAY DIFFRACTIONr_dihedral_angle_other_6_deg26.01201
X-RAY DIFFRACTIONr_chiral_restr0.0730.2408
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.023629
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02697
X-RAY DIFFRACTIONr_nbd_refined0.1890.2597
X-RAY DIFFRACTIONr_symmetry_nbd_other0.170.22798
X-RAY DIFFRACTIONr_nbtor_refined0.1530.21473
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0680.21329
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1590.2304
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0210.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1220.218
X-RAY DIFFRACTIONr_nbd_other0.1470.2127
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1870.236
X-RAY DIFFRACTIONr_mcbond_it1.1051.6971574
X-RAY DIFFRACTIONr_mcbond_other1.1071.6971574
X-RAY DIFFRACTIONr_mcangle_it1.4092.5551979
X-RAY DIFFRACTIONr_mcangle_other1.4092.5551980
X-RAY DIFFRACTIONr_scbond_it1.6321.9621594
X-RAY DIFFRACTIONr_scbond_other1.6321.9631595
X-RAY DIFFRACTIONr_scangle_it1.912.8452320
X-RAY DIFFRACTIONr_scangle_other1.912.8462321
X-RAY DIFFRACTIONr_lrange_it3.43622.1253608
X-RAY DIFFRACTIONr_lrange_other2.69521.0243499
X-RAY DIFFRACTIONr_rigid_bond_restr3.1836164
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.54-1.580.2962860.2473794X-RAY DIFFRACTION99.7799
1.58-1.6230.2582710.2153644X-RAY DIFFRACTION99.9489
1.623-1.670.233000.1883539X-RAY DIFFRACTION100
1.67-1.7220.2572440.23481X-RAY DIFFRACTION99.9732
1.722-1.7780.2162560.1523396X-RAY DIFFRACTION99.9726
1.778-1.8410.1962540.1283252X-RAY DIFFRACTION99.886
1.841-1.910.3552230.2882948X-RAY DIFFRACTION93.5674
1.91-1.9880.3032110.2882779X-RAY DIFFRACTION92.0566
1.988-2.0760.2882240.2472830X-RAY DIFFRACTION97.2302
2.076-2.1770.1842360.1212725X-RAY DIFFRACTION98.1113
2.177-2.2950.3011730.262437X-RAY DIFFRACTION91.2268
2.295-2.4340.1641980.1052509X-RAY DIFFRACTION99.9262
2.434-2.6020.1731840.0982360X-RAY DIFFRACTION99.8822
2.602-2.810.1981640.1252216X-RAY DIFFRACTION99.4567
2.81-3.0780.1571500.1042056X-RAY DIFFRACTION99.9547
3.078-3.4410.1751450.1281850X-RAY DIFFRACTION99.7999
3.441-3.9710.1681210.1411615X-RAY DIFFRACTION98.0791
3.971-4.860.131360.1131404X-RAY DIFFRACTION99.9351
4.86-6.8590.191760.1731113X-RAY DIFFRACTION99.8321
6.859-73.130.217620.179639X-RAY DIFFRACTION99.1513

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