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- PDB-7rwh: Crystal structure of human methionine adenosyltransferase 2A (MAT... -

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Basic information

Entry
Database: PDB / ID: 7rwh
TitleCrystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor AGI-41998
ComponentsS-adenosylmethionine synthase isoform type-2
KeywordsTRANSFERASE/INHIBITOR / METHIONINE ADENOSYLTRANSFERASE / SAM / ALLOSTERIC INHIBITOR / TRANSFERASE / TRANSFERASE-INHIBITOR COMPLEX
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
Chem-7UI / S-ADENOSYLMETHIONINE / S-adenosylmethionine synthase isoform type-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.17 Å
AuthorsJin, L. / Padyana, A.K.
Funding support1items
OrganizationGrant numberCountry
Other private
Citation
Journal: J.Med.Chem. / Year: 2022
Title: Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads.
Authors: Li, M. / Konteatis, Z. / Nagaraja, N. / Chen, Y. / Zhou, S. / Ma, G. / Gross, S. / Marjon, K. / Hyer, M.L. / Mandley, E. / Lein, M. / Padyana, A.K. / Jin, L. / Tong, S. / Peters, R. / ...Authors: Li, M. / Konteatis, Z. / Nagaraja, N. / Chen, Y. / Zhou, S. / Ma, G. / Gross, S. / Marjon, K. / Hyer, M.L. / Mandley, E. / Lein, M. / Padyana, A.K. / Jin, L. / Tong, S. / Peters, R. / Murtie, J. / Travins, J. / Medeiros, M. / Liu, P. / Frank, V. / Judd, E.T. / Biller, S.A. / Marks, K.M. / Sui, Z. / Reznik, S.K.
#1: Journal: J.MED.CHEM. / Year: 2021
Title: DISCOVERY OF AG-270, A FIRST-IN-CLASS ORAL MAT2A INHIBITOR DISCOVERY OF AG-270, A FIRST-IN-CLASS ORAL MAT2A INHIBITOR
Authors: Konteatis, Z. / Travins, J.
History
DepositionAug 19, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 30, 2022Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Apr 6, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)45,39813
Polymers43,8081
Non-polymers1,59112
Water9,548530
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)90,79726
Polymers87,6152
Non-polymers3,18124
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area10170 Å2
ΔGint-78 kcal/mol
Surface area25460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.560, 94.110, 116.690
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-412-

MG

21A-601-

HOH

31A-624-

HOH

41A-650-

HOH

51A-861-

HOH

61A-897-

HOH

71A-997-

HOH

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 43807.703 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 , 8 types, 542 molecules

#2: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE / S-Adenosyl methionine


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#3: Chemical ChemComp-7UI / 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-[2,2,2-tris(fluoranyl)ethylamino]pyrido[4,3-d]pyrimidin-7-ol


Mass: 505.287 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H16BrF3N4O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400 / Polyethylene glycol


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#7: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#8: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 530 / 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: 2.15 Å3/Da / Density % sol: 42.75 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8
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: 21-ID-D / Wavelength: 1.1271 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1271 Å / Relative weight: 1
ReflectionResolution: 1.17→36.63 Å / Num. obs: 116890 / % possible obs: 92.3 % / Redundancy: 11.6 % / Biso Wilson estimate: 9.25 Å2 / Rmerge(I) obs: 0.114 / Net I/σ(I): 12.1
Reflection shellResolution: 1.17→1.2 Å / Rmerge(I) obs: 0.675 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 3998

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2P02

2p02


Resolution: 1.17→35.95 Å / SU ML: 0.0743 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 13.1522
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1336 5743 4.91 %
Rwork0.1138 111106 -
obs0.1147 116849 92.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 14.78 Å2
Refinement stepCycle: LAST / Resolution: 1.17→35.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2996 0 100 530 3626
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01043362
X-RAY DIFFRACTIONf_angle_d1.21714571
X-RAY DIFFRACTIONf_chiral_restr0.0975492
X-RAY DIFFRACTIONf_plane_restr0.0096598
X-RAY DIFFRACTIONf_dihedral_angle_d19.13451278
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.17-1.180.2421610.21851423X-RAY DIFFRACTION35.54
1.18-1.20.2195870.20391906X-RAY DIFFRACTION47.33
1.2-1.210.2221230.1912391X-RAY DIFFRACTION59.67
1.21-1.230.20561540.17622741X-RAY DIFFRACTION69.74
1.23-1.240.19081660.16833088X-RAY DIFFRACTION77.87
1.24-1.260.19551840.16283439X-RAY DIFFRACTION86.3
1.26-1.280.16641720.15643724X-RAY DIFFRACTION93.18
1.28-1.30.16511880.14933887X-RAY DIFFRACTION96.98
1.3-1.320.16532120.13753939X-RAY DIFFRACTION99.14
1.32-1.340.15222060.12743974X-RAY DIFFRACTION99.81
1.34-1.360.1322030.13173996X-RAY DIFFRACTION99.95
1.36-1.390.14542280.12873982X-RAY DIFFRACTION99.95
1.39-1.410.14582030.12623973X-RAY DIFFRACTION99.95
1.41-1.440.14112310.12183981X-RAY DIFFRACTION99.93
1.44-1.470.13771970.11984030X-RAY DIFFRACTION99.88
1.47-1.510.12692070.11263958X-RAY DIFFRACTION99.98
1.51-1.550.11981980.10944020X-RAY DIFFRACTION99.98
1.55-1.590.13172200.10764013X-RAY DIFFRACTION99.88
1.59-1.630.13552050.10633975X-RAY DIFFRACTION99.9
1.63-1.690.12312060.10924019X-RAY DIFFRACTION99.88
1.69-1.750.13431970.10724016X-RAY DIFFRACTION99.93
1.75-1.820.1142100.10744017X-RAY DIFFRACTION100
1.82-1.90.12452090.10574022X-RAY DIFFRACTION100
1.9-20.12732230.10124014X-RAY DIFFRACTION100
2-2.130.11672290.0984026X-RAY DIFFRACTION100
2.13-2.290.11231750.09844089X-RAY DIFFRACTION100
2.29-2.520.12152050.09744039X-RAY DIFFRACTION99.79
2.52-2.880.13332260.10314054X-RAY DIFFRACTION99.74
2.89-3.630.12862210.1034107X-RAY DIFFRACTION99.95
3.63-35.950.13351970.12124263X-RAY DIFFRACTION99.55
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.447623644481-0.2225504026010.2018168116940.418805259777-0.1499646906580.660494541129-0.0292034170364-0.009625741914130.01304626460450.02704061948750.0162540184621-0.0245530462134-0.02030758925620.0208097916490.01180517050490.06658874733-0.004479313166370.001755625059260.0649407879927-0.005600825868850.07659538145147.67301852696.18445919927-19.1967803171
21.51880362165-1.594556128960.08564617839134.00616143198-0.255770407841.78428056255-0.0475330581494-0.02469733393350.09158466670020.1015324376690.0291621746712-0.0783482469162-0.0556093852010.1062229205710.0285111121860.0817757423888-0.0130930558892-0.007539583751460.0930592520978-0.003208971113210.07292838112987.1826184029215.9437534602-5.53310977082
30.188858753688-0.0900301303655-0.01424929063130.269890482414-0.01011590587510.180094192472-0.001965331091480.00672565567060.022669046509-0.01205074813310.00322965452685-0.00841985051298-0.0177066239852-0.00219539751141-0.002493311453030.0720205237782-0.00552281515871-0.001115214446810.07259641053560.001931915807630.07645582210145.028482030179.74915944453-28.8485542799
41.57421629707-0.6845420346190.9745938888690.566725873923-0.854508621492.954826406180.08741443946410.180489263553-0.0596263410528-0.119596510879-0.00695826936828-0.02695433103760.2570795752430.163626319797-0.1035194339010.108214326167-0.001943425019610.01362447670310.09657855425440.005719605284250.11117705436321.3213945103-5.65559406863-39.206982439
50.8303324735990.1443063316950.4837628301010.922019786171-0.3646854349381.31677858217-0.05437782994450.01875167874010.0733936926582-2.44832166373E-50.0388541793593-0.123427681702-0.07715304220940.101532108318-0.01510045417770.0773524525557-0.0157162698658-0.001464171290830.073381966457-0.001199374729870.10135457844718.84141661727.88153751284-28.809267983
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 78 )
2X-RAY DIFFRACTION2chain 'A' and (resid 79 through 104 )
3X-RAY DIFFRACTION3chain 'A' and (resid 105 through 341 )
4X-RAY DIFFRACTION4chain 'A' and (resid 342 through 364 )
5X-RAY DIFFRACTION5chain 'A' and (resid 365 through 395 )

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