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- PDB-8xam: Co-crystal structure of compound 7 in complex with MAT2A -

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Basic information

Entry
Database: PDB / ID: 8xam
TitleCo-crystal structure of compound 7 in complex with MAT2A
ComponentsS-adenosylmethionine synthase isoform type-2
KeywordsTRANSFERASE / MAT2A inhibitor
Function / homology
Function and homology information


methionine adenosyltransferase complex / methionine adenosyltransferase / methionine adenosyltransferase activity / S-adenosylmethionine biosynthetic process / Methylation / protein heterooligomerization / protein hexamerization / small molecule binding / cellular response to leukemia inhibitory factor / one-carbon metabolic process ...methionine adenosyltransferase complex / methionine adenosyltransferase / methionine adenosyltransferase activity / S-adenosylmethionine biosynthetic process / Methylation / protein heterooligomerization / protein hexamerization / small molecule binding / cellular response to leukemia inhibitory factor / one-carbon metabolic process / ATP binding / identical protein binding / metal ion 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: 1.3 Å
AuthorsGao, F. / Ding, X.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2024
Title: Discovery of novel MAT2A inhibitors by an allosteric site-compatible fragment growing approach.
Authors: Gao, F. / Ding, X. / Cao, Z. / Zhu, W. / Fan, Y. / Steurer, B. / Wang, H. / Cai, X. / Zhang, M. / Aliper, A. / Ren, F. / Ding, X. / Zhavoronkov, A.
History
DepositionDec 4, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 28, 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
B: S-adenosylmethionine synthase isoform type-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,4715
Polymers84,0042
Non-polymers1,4673
Water19,7801098
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6660 Å2
ΔGint-25 kcal/mol
Surface area24280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.968, 94.043, 116.892
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number5
Space group name H-MI121
Components on special symmetry positions
IDModelComponents
11A-856-

HOH

21A-881-

HOH

31B-876-

HOH

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Components

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


Mass: 42001.773 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAT2A, AMS2, MATA2 / Production host: Escherichia phage EcWhh-1 (virus) / References: UniProt: P31153, methionine adenosyltransferase
#2: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE / S-Adenosyl methionine


Mass: 398.437 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H22N6O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-XRH / 2-[3-[7-chloranyl-4-(dimethylamino)-2-oxidanylidene-quinazolin-1-yl]phenoxy]-~{N}-[3-[7-chloranyl-4-(dimethylamino)-2-oxidanylidene-quinazolin-1-yl]phenyl]ethanamide / 3-CARBAMIMIDOYL-1-(PYRIDIN-3-YLCARBAMOYLMETHYL)-1H-INDOLE-7-CARBOXYLIC ACID PYRIDIN-3-YLAMIDE


Mass: 670.545 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H29Cl2N7O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1098 / Source method: isolated from a natural source / Formula: H2O
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: 2.22 Å3/Da / Density % sol: 44.68 %
Crystal growTemperature: 297 K / Method: vapor diffusion, hanging drop
Details: 0.2 M LiCl, 0.1 M Tris pH 8.0, (18%-20%) PEG6000, 10% Ethylene Glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 18-ID / Wavelength: 1.1807 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 11, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1807 Å / Relative weight: 1
ReflectionResolution: 1.3→47.02 Å / Num. obs: 169065 / % possible obs: 94.1 % / Redundancy: 6.9 % / CC1/2: 1 / Net I/σ(I): 25.9
Reflection shellResolution: 1.3→1.32 Å / Num. unique obs: 7991 / CC1/2: 0.931

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.3→40.119 Å / Cor.coef. Fo:Fc: 0.982 / Cor.coef. Fo:Fc free: 0.975 / SU B: 0.529 / SU ML: 0.023 / Cross valid method: FREE R-VALUE / ESU R: 0.038 / ESU R Free: 0.041
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1427 8426 4.984 %
Rwork0.1213 160636 -
all0.122 --
obs-169062 93.948 %
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: 11.625 Å2
Baniso -1Baniso -2Baniso -3
1-0.491 Å20 Å20.014 Å2
2---0.241 Å20 Å2
3----0.25 Å2
Refinement stepCycle: LAST / Resolution: 1.3→40.119 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5882 0 101 1098 7081
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0136323
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175985
X-RAY DIFFRACTIONr_angle_refined_deg1.9991.6668621
X-RAY DIFFRACTIONr_angle_other_deg1.5951.59713813
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8825808
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.95722.212321
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.373151070
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.0151542
X-RAY DIFFRACTIONr_chiral_restr0.1180.2813
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.027223
X-RAY DIFFRACTIONr_gen_planes_other0.0050.021411
X-RAY DIFFRACTIONr_nbd_refined0.2330.21323
X-RAY DIFFRACTIONr_symmetry_nbd_other0.190.26016
X-RAY DIFFRACTIONr_nbtor_refined0.1780.22995
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0880.22975
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2830.2822
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.2360.25
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1190.215
X-RAY DIFFRACTIONr_nbd_other0.2040.266
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2320.269
X-RAY DIFFRACTIONr_mcbond_it1.0070.9523098
X-RAY DIFFRACTIONr_mcbond_other1.0070.9523098
X-RAY DIFFRACTIONr_mcangle_it1.4621.4323875
X-RAY DIFFRACTIONr_mcangle_other1.4621.4323876
X-RAY DIFFRACTIONr_scbond_it2.1571.1893225
X-RAY DIFFRACTIONr_scbond_other2.1571.1893225
X-RAY DIFFRACTIONr_scangle_it3.1841.7014721
X-RAY DIFFRACTIONr_scangle_other3.1831.7014722
X-RAY DIFFRACTIONr_lrange_it5.30413.9237778
X-RAY DIFFRACTIONr_lrange_other4.83412.4297354
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3-1.3340.1856320.16311375X-RAY DIFFRACTION90.1765
1.334-1.370.2024750.16111230X-RAY DIFFRACTION90.596
1.37-1.410.1775920.14610851X-RAY DIFFRACTION90.8968
1.41-1.4530.1575850.13910598X-RAY DIFFRACTION91.709
1.453-1.5010.1395670.12710389X-RAY DIFFRACTION92.2145
1.501-1.5540.1385560.1210078X-RAY DIFFRACTION92.7599
1.554-1.6120.1274920.1129820X-RAY DIFFRACTION93.2116
1.612-1.6780.1384630.1129494X-RAY DIFFRACTION93.7041
1.678-1.7530.1334590.1139193X-RAY DIFFRACTION94.221
1.753-1.8380.1424190.1158838X-RAY DIFFRACTION94.856
1.838-1.9380.1454530.1178357X-RAY DIFFRACTION95.3566
1.938-2.0550.1374430.1178031X-RAY DIFFRACTION95.7731
2.055-2.1970.1274280.1137512X-RAY DIFFRACTION96.3125
2.197-2.3730.134110.117051X-RAY DIFFRACTION96.7834
2.373-2.5990.1063530.1016546X-RAY DIFFRACTION97.128
2.599-2.9050.1433000.1095961X-RAY DIFFRACTION97.7823
2.905-3.3540.1342510.1215329X-RAY DIFFRACTION98.1876
3.354-4.1050.152400.1134519X-RAY DIFFRACTION98.4281
4.105-5.7960.1511900.1323511X-RAY DIFFRACTION98.9572

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