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- PDB-7rwg: "Crystal structure of human methionine adenosyltransferase 2A (MA... -

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Basic information

Entry
Database: PDB / ID: 7rwg
Title"Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor AGI-43192
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-7UN / S-ADENOSYLMETHIONINE / S-adenosylmethionine synthase isoform type-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 0.97 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)45,12910
Polymers43,8081
Non-polymers1,3219
Water10,989610
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)90,25820
Polymers87,6152
Non-polymers2,64218
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area9160 Å2
ΔGint-35 kcal/mol
Surface area25480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.990, 93.720, 116.190
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-598-

HOH

21A-632-

HOH

31A-872-

HOH

41A-1078-

HOH

51A-1090-

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 , 6 types, 619 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-CL / CHLORIDE ION / Chloride


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


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-7UN / (8R)-8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one


Mass: 484.861 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H16ClF3N6O / Feature type: SUBJECT OF INVESTIGATION
#6: 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
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 610 / 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: 2.11 Å3/Da / Density % sol: 41.78 %
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: CLSI / Beamline: 08B1-1 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 7, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 0.97→46.86 Å / Num. obs: 207397 / % possible obs: 95.5 % / Redundancy: 7.6 % / Biso Wilson estimate: 6.35 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 19.6
Reflection shellResolution: 0.97→0.99 Å / Rmerge(I) obs: 0.863 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 9856 / % possible all: 91.9

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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: 0.97→39.95 Å / SU ML: 0.0951 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 12.0123
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1357 10109 4.88 %
Rwork0.1225 196961 -
obs0.1231 207070 95.14 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 10.94 Å2
Refinement stepCycle: LAST / Resolution: 0.97→39.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2991 0 88 610 3689
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00943382
X-RAY DIFFRACTIONf_angle_d1.14164607
X-RAY DIFFRACTIONf_chiral_restr0.0921495
X-RAY DIFFRACTIONf_plane_restr0.0098605
X-RAY DIFFRACTIONf_dihedral_angle_d21.29291290
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
0.97-0.980.26632980.28296277X-RAY DIFFRACTION91.5
0.98-0.990.27053280.25756271X-RAY DIFFRACTION91.81
0.99-10.23943260.24236338X-RAY DIFFRACTION92.34
1-1.020.24833100.22456332X-RAY DIFFRACTION92.4
1.02-1.030.19133200.2056361X-RAY DIFFRACTION92.65
1.03-1.040.21413030.19566397X-RAY DIFFRACTION92.75
1.04-1.060.19493410.18246351X-RAY DIFFRACTION93.14
1.06-1.080.2053390.1716365X-RAY DIFFRACTION93.12
1.08-1.090.16773450.15296447X-RAY DIFFRACTION93.62
1.09-1.110.13893430.14236379X-RAY DIFFRACTION93.66
1.11-1.130.13993250.13446459X-RAY DIFFRACTION94.05
1.13-1.150.14183260.13266452X-RAY DIFFRACTION94.11
1.15-1.170.143740.13566506X-RAY DIFFRACTION94.56
1.17-1.20.1293310.13176449X-RAY DIFFRACTION94.73
1.2-1.220.14863570.13226520X-RAY DIFFRACTION94.59
1.22-1.250.14723290.12696506X-RAY DIFFRACTION95.05
1.25-1.280.12493590.12396596X-RAY DIFFRACTION95.46
1.28-1.320.12693280.11566545X-RAY DIFFRACTION95.51
1.32-1.360.13273470.11676608X-RAY DIFFRACTION96.04
1.36-1.40.12293750.11386575X-RAY DIFFRACTION96.01
1.4-1.450.11793350.10986672X-RAY DIFFRACTION96.5
1.45-1.510.11263460.10466658X-RAY DIFFRACTION96.73
1.51-1.580.10863430.10096712X-RAY DIFFRACTION96.98
1.58-1.660.11953150.09966774X-RAY DIFFRACTION97.23
1.66-1.760.10863300.09986734X-RAY DIFFRACTION97.45
1.76-1.90.11283380.09876832X-RAY DIFFRACTION97.86
1.9-2.090.11073340.09856820X-RAY DIFFRACTION98.11
2.09-2.390.11563530.09926892X-RAY DIFFRACTION98.56
2.39-3.010.1233500.10526970X-RAY DIFFRACTION98.68
3.01-39.950.14133610.12017163X-RAY DIFFRACTION98.58
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)
10.220592720637-0.07370593173180.01958046953920.268276867352-0.03747632807970.323268547128-0.0178981020706-0.00244029371430.008627207237970.02067795834740.0113064068326-0.0272221987127-0.02054587973460.02841141965280.008874785067380.0430897535877-0.000782261277788.8228148301E-50.0474660115221-0.003906545524160.05100064464098.151847594525.84893003146-18.2591979916
20.65551904279-0.356182182818-0.02369381967761.37097434327-0.01096529546820.805752541328-0.0199243625307-0.00824968431170.07601138699940.06622873278840.0185022433405-0.028034444785-0.04208902919050.1093465036460.0003236360300460.0656097049303-0.003430083753-0.005634714862970.0717722364271-0.002583677506040.05273343528797.3976764702815.8570261574-5.5689799076
30.176751242231-0.0910230949179-0.008925190424310.29654339044-0.02175935299440.197155627270.001872064754330.006120866966980.0330668224014-0.00716831140095-0.00100717163773-0.0130435670657-0.02833907903720.00322633798158-0.001145697161520.0462341361865-0.00658217096722-0.0004317403656980.05111262342740.0008710725579150.05682972619854.2363463730712.3431144972-26.1432084074
41.02971300850.241980171484-0.2913830627160.627305473339-0.1113287288070.951771387346-0.01527893259810.1011325966660.122772020323-0.0834934201130.04427275175440.0210653778715-0.1060784040680.003380542088560.009892869760340.0833288053211-0.00214943980851-0.0007475865481880.06353309314520.01892017558780.0824827390329-4.6457502929426.4696877296-36.1140522357
50.217459828385-0.0793025545217-0.005488958492090.1713201006620.0277684947130.1649767492640.00478034816480.0272206143970.00553037339772-0.0264972432398-0.00217282487331-0.0123740127466-0.005999065857310.0173601251835-0.001042011800540.0486402549448-0.002207768809130.002751169081610.04631281124990.003642509458510.048342665068.467122480371.93189913004-31.556722795
60.568604229644-0.2695905415480.2730818280550.357576913481-0.2631233864451.507513607010.0316028848530.122406425361-0.0330669338165-0.0763868470538-0.0193213680257-0.008439111910480.1041139883860.049628408876-0.0320729618460.07752500605210.003808715755520.00922857079840.08677492909610.002116664039430.089778823924721.2098386765-5.65402400163-39.0877027089
70.4252088012030.05468039945360.03462324831340.313861993013-0.1762349885740.726577820491-0.02190625492560.04140908840730.0650483199645-0.02957451334940.0115027130137-0.0890713512378-0.05629438479980.0741850771561-0.02268585481340.0677532571856-0.01133791018580.003887964664420.06959528329010.0007563216002420.084924589412918.88868146467.80218930362-29.3574011801
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 12 through 78 )
2X-RAY DIFFRACTION2chain 'A' and (resid 79 through 104 )
3X-RAY DIFFRACTION3chain 'A' and (resid 105 through 224 )
4X-RAY DIFFRACTION4chain 'A' and (resid 225 through 244 )
5X-RAY DIFFRACTION5chain 'A' and (resid 245 through 341 )
6X-RAY DIFFRACTION6chain 'A' and (resid 342 through 364 )
7X-RAY DIFFRACTION7chain 'A' and (resid 365 through 395 )

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