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

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Basic information

Entry
Database: PDB / ID: 7kdb
TitleCrystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor compound 35
ComponentsS-adenosylmethionine synthase isoform type-2
KeywordsTRANSFERASE/Inhibitor / ETHIONINE 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
S-ADENOSYLMETHIONINE / Chem-WBS / S-adenosylmethionine synthase isoform type-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.24 Å
AuthorsPadyana, A. / Jin, L.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion.
Authors: Konteatis, Z. / Travins, J. / Gross, S. / Marjon, K. / Barnett, A. / Mandley, E. / Nicolay, B. / Nagaraja, R. / Chen, Y. / Sun, Y. / Liu, Z. / Yu, J. / Ye, Z. / Jiang, F. / Wei, W. / Fang, C. ...Authors: Konteatis, Z. / Travins, J. / Gross, S. / Marjon, K. / Barnett, A. / Mandley, E. / Nicolay, B. / Nagaraja, R. / Chen, Y. / Sun, Y. / Liu, Z. / Yu, J. / Ye, Z. / Jiang, F. / Wei, W. / Fang, C. / Gao, Y. / Kalev, P. / Hyer, M.L. / DeLaBarre, B. / Jin, L. / Padyana, A.K. / Dang, L. / Murtie, J. / Biller, S.A. / Sui, Z. / Marks, K.M.
History
DepositionOct 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 21, 2021Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)45,13810
Polymers43,8081
Non-polymers1,3309
Water9,188510
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)90,27620
Polymers87,6152
Non-polymers2,66118
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area9440 Å2
ΔGint-45 kcal/mol
Surface area24560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.110, 94.027, 116.795
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-636-

HOH

21A-650-

HOH

31A-659-

HOH

41A-852-

HOH

51A-988-

HOH

61A-995-

HOH

71A-1004-

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 , 7 types, 519 molecules

#2: Chemical ChemComp-WBS / 6-(4-hydroxyphenyl)-2,3-diphenyl-5-[(1H-pyrazol-3-yl)amino]pyrazolo[1,5-a]pyrimidin-7(4H)-one


Mass: 460.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H20N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER / Tris


Mass: 122.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#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: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE / S-Adenosyl methionine


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 510 / 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: 2.13 Å3/Da / Density % sol: 42.37 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: 0.2 M Lithium Chloride, 0.1 M Tris PH 7.8, 24% PEG 6000, 10% Ethylene Glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97922 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97922 Å / Relative weight: 1
ReflectionResolution: 1.24→30.88 Å / Num. obs: 105562 / % possible obs: 99.6 % / Redundancy: 4.8 % / Biso Wilson estimate: 8.25 Å2 / Rmerge(I) obs: 0.091 / Net I/σ(I): 16.2
Reflection shellResolution: 1.24→1.29 Å / Rmerge(I) obs: 0.451 / Mean I/σ(I) obs: 3.5 / Num. unique obs: 10311 / % possible all: 96.8

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2P02

2p02


Resolution: 1.24→30.88 Å / SU ML: 0.0836 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 12.1465
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1384 5152 4.88 %
Rwork0.1264 100398 -
obs0.127 105550 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 12.2 Å2
Refinement stepCycle: LAST / Resolution: 1.24→30.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2960 0 90 510 3560
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01143392
X-RAY DIFFRACTIONf_angle_d1.2064640
X-RAY DIFFRACTIONf_chiral_restr0.0921506
X-RAY DIFFRACTIONf_plane_restr0.0089616
X-RAY DIFFRACTIONf_dihedral_angle_d19.99171347
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.24-1.250.2041530.2073229X-RAY DIFFRACTION96.93
1.25-1.270.1931880.19173290X-RAY DIFFRACTION99.94
1.27-1.290.19621970.18023318X-RAY DIFFRACTION100
1.29-1.30.1721600.17363301X-RAY DIFFRACTION100
1.3-1.320.18541660.16983323X-RAY DIFFRACTION100
1.32-1.340.16751760.16423335X-RAY DIFFRACTION100
1.34-1.360.16811660.16033310X-RAY DIFFRACTION100
1.36-1.380.15561610.15353357X-RAY DIFFRACTION100
1.38-1.40.18521690.1523332X-RAY DIFFRACTION100
1.4-1.420.16741560.14943362X-RAY DIFFRACTION100
1.42-1.440.18091510.1643325X-RAY DIFFRACTION99.94
1.44-1.470.17341820.153320X-RAY DIFFRACTION100
1.47-1.50.14151550.13583335X-RAY DIFFRACTION100
1.5-1.530.13831650.12763330X-RAY DIFFRACTION100
1.53-1.560.1331380.11963385X-RAY DIFFRACTION100
1.56-1.60.12441680.11753312X-RAY DIFFRACTION99.97
1.6-1.640.13741770.11433332X-RAY DIFFRACTION99.86
1.64-1.680.11491690.11273361X-RAY DIFFRACTION100
1.68-1.730.13531690.11023343X-RAY DIFFRACTION100
1.73-1.790.12932070.10983326X-RAY DIFFRACTION100
1.79-1.850.12121760.11073318X-RAY DIFFRACTION100
1.85-1.930.11721760.1123363X-RAY DIFFRACTION99.97
1.93-2.020.11131990.10843340X-RAY DIFFRACTION100
2.02-2.120.12521780.10763344X-RAY DIFFRACTION99.94
2.12-2.250.10331730.10713363X-RAY DIFFRACTION100
2.25-2.430.1341730.10873393X-RAY DIFFRACTION99.97
2.43-2.670.12731970.11323354X-RAY DIFFRACTION99.8
2.67-3.060.1221580.11373429X-RAY DIFFRACTION99.94
3.06-3.850.14191550.1153449X-RAY DIFFRACTION99.94
3.85-30.880.14651940.14223519X-RAY DIFFRACTION98.75
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)
10.3448273355-0.1160032960030.0977222704260.359100092712-0.04373049554610.267789685748-0.0176984027199-0.01756779339110.007935886333170.01260669552920.0168079923898-0.0215239885534-0.01682462038090.0336879114575-5.67829385313E-50.04681520645980.00034340478005-0.0003282210941780.0533239662825-0.004200344128750.052169727289.536642555085.23499413501-16.2324802278
20.1149710685120.121866460573-0.001893538256210.1757653428730.07904569559280.238863173492-0.0278664995285-0.0189884525970.07343953982850.03558578001020.0230307944689-0.0428560532694-0.0504845154830.1161943776862.03926672535E-50.0819109652519-0.00125366908512-0.005131160982780.0900287633221-0.00217358935920.06869529514177.3195681425316.0667318929-5.60998503132
30.134666062936-0.1745992066330.0254740602440.477543924714-0.09791088439040.248224749237-0.00243754510340.003556077719160.0129342249481-0.0151601651171-0.00914564927341-0.04840565180940.009417137321620.03611680853492.74932522503E-50.0450294812315-0.008477088870670.0002862803692580.0610118163680.001307469477760.065490803134411.92093661572.11971626885-23.9382962356
40.517306600867-0.1206962837160.08920711977360.771023538310.01257677774070.3166974559850.01453918145860.03034927860220.0857165833691-0.07072944004450.006187826461350.0150037739602-0.0818590888560.00264238721336-0.0002059070154650.06490606964170.0008743705801470.0007338881760070.05466092270420.0153308397120.0733328622704-3.9245592680723.8947808677-30.5809233312
50.302101748555-0.165120310909-0.01707876703810.2725029830670.04933192714520.212641904030.006504432267630.0264116678029-0.000702065738435-0.0381297807654-0.00615549669044-0.011034955091-0.001554002774510.02366473978285.18785622125E-60.0584094516395-0.006447647725180.003991598033320.05240363440840.00473282066220.05583301796328.278336542271.92456609837-31.7621120737
60.166342848473-0.0618971147548-0.0290045791820.141492685582-0.1090633275650.1227105834720.04098363782880.165911443449-0.0104183304411-0.130189172938-0.0559467949056-0.1121787993990.1218161578910.132632522819-0.0001402949022130.1214059761780.01857629151730.02037630323590.1102986036030.003664526654240.096127597138221.4052109317-5.34220168492-38.6366618844
70.3732008727090.0204335203970.1953403451430.295537064004-0.1805304170190.243506516992-0.04968224015880.05871471370170.0943766395035-0.03999567781860.0199859457197-0.111162647723-0.05602183420870.0782484090556-0.002073923500840.0795304721907-0.01561232681190.01019167725610.08318529248270.002622374240070.095884752560319.44613618217.36946874183-30.3281024609
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 15 through 78 )
2X-RAY DIFFRACTION2chain 'A' and (resid 79 through 104 )
3X-RAY DIFFRACTION3chain 'A' and (resid 105 through 169 )
4X-RAY DIFFRACTION4chain 'A' and (resid 170 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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