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- PDB-8qe2: Crystal structure of human MAT2a bound to S-Adenosylmethionine an... -

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Basic information

Entry
Database: PDB / ID: 8qe2
TitleCrystal structure of human MAT2a bound to S-Adenosylmethionine and Compound 21
ComponentsS-adenosylmethionine synthase isoform type-2
KeywordsTRANSFERASE / S-Adenosylmethionine biosynthesis / allosteric inhibitor
Function / homology
Function and homology information


methionine adenosyltransferase complex / methionine adenosyltransferase / methionine adenosyltransferase activity / S-adenosylmethionine biosynthetic process / Methylation / protein heterooligomerization / cellular response to methionine / protein hexamerization / small molecule binding / positive regulation of TORC1 signaling ...methionine adenosyltransferase complex / methionine adenosyltransferase / methionine adenosyltransferase activity / S-adenosylmethionine biosynthetic process / Methylation / protein heterooligomerization / cellular response to methionine / protein hexamerization / small molecule binding / positive regulation of TORC1 signaling / 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: 1.109 Å
AuthorsSchimpl, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Development of a Series of Pyrrolopyridone MAT2A Inhibitors.
Authors: Atkinson, S.J. / Bagal, S.K. / Argyrou, A. / Askin, S. / Cheung, T. / Chiarparin, E. / Coen, M. / Collie, I.T. / Dale, I.L. / De Fusco, C. / Dillman, K. / Evans, L. / Feron, L.J. / Foster, A. ...Authors: Atkinson, S.J. / Bagal, S.K. / Argyrou, A. / Askin, S. / Cheung, T. / Chiarparin, E. / Coen, M. / Collie, I.T. / Dale, I.L. / De Fusco, C. / Dillman, K. / Evans, L. / Feron, L.J. / Foster, A.J. / Grondine, M. / Kantae, V. / Lamont, G.M. / Lamont, S. / Lynch, J.T. / Nilsson Lill, S. / Robb, G.R. / Saeh, J. / Schimpl, M. / Scott, J.S. / Smith, J. / Srinivasan, B. / Tentarelli, S. / Vazquez-Chantada, M. / Wagner, D. / Walsh, J.J. / Watson, D. / Williamson, B.
History
DepositionAug 30, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 20, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: S-adenosylmethionine synthase isoform type-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,7823
Polymers43,9361
Non-polymers8462
Water7,350408
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)89,5636
Polymers87,8722
Non-polymers1,6924
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565-x,-y+1,z1
Buried area6740 Å2
ΔGint-26 kcal/mol
Surface area25190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.160, 94.010, 116.647
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-611-

HOH

21A-629-

HOH

31A-897-

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: 43935.828 Da / Num. of mol.: 1 / Fragment: full length protein
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
#2: Chemical ChemComp-U7X / 4-[4-[bis(fluoranyl)methoxy]phenyl]-3-cyclopropyl-6-(2-methylindazol-5-yl)-2~{H}-pyrazolo[4,3-b]pyridin-5-one


Mass: 447.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H19F2N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


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


Mass: 18.015 Da / Num. of mol.: 408 / 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: 2.13 Å3/Da / Density % sol: 42.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8
Details: 8-12 % PEG 8000, 8-12 % ethylene glycol, 0.1 M Hepes pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.97004 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 26, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97004 Å / Relative weight: 1
ReflectionResolution: 1.109→58.85 Å / Num. obs: 132342 / % possible obs: 90.5 % / Redundancy: 5.7 % / Rmerge(I) obs: 0.048 / Rpim(I) all: 0.021 / Rrim(I) all: 0.052 / Net I/σ(I): 16.2
Reflection shellResolution: 1.114→1.159 Å / % possible obs: 40.8 % / Redundancy: 1.8 % / Rmerge(I) obs: 0.306 / Num. measured all: 12132 / Num. unique obs: 6595 / Rpim(I) all: 0.269 / Rrim(I) all: 0.41 / Net I/σ(I) obs: 1.9

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (24-FEB-2021)refinement
STARANISOdata scaling
XDSdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.109→58.85 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.911 / SU R Cruickshank DPI: 0.032 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.033 / SU Rfree Blow DPI: 0.035 / SU Rfree Cruickshank DPI: 0.034
RfactorNum. reflection% reflectionSelection details
Rfree0.1814 6471 4.89 %RANDOM
Rwork0.1626 ---
obs0.1635 132342 89.7 %-
Displacement parametersBiso mean: 11.01 Å2
Baniso -1Baniso -2Baniso -3
1--0.1529 Å20 Å20 Å2
2---0.1951 Å20 Å2
3---0.348 Å2
Refine analyzeLuzzati coordinate error obs: 0.12 Å
Refinement stepCycle: LAST / Resolution: 1.109→58.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2964 0 60 408 3432
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0083132HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.994256HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1104SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes536HARMONIC5
X-RAY DIFFRACTIONt_it3132HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion5.16
X-RAY DIFFRACTIONt_other_torsion14.38
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion401SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3486SEMIHARMONIC4
LS refinement shellResolution: 1.11→1.13 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2476 108 4.08 %
Rwork0.235 2539 -
all0.2355 2647 -
obs--28.2 %
Refinement TLS params.Method: refined / Origin x: 8.0917 Å / Origin y: 38.8468 Å / Origin z: 25.8913 Å
111213212223313233
T-0.0085 Å20.0042 Å2-0.0024 Å2--0.0074 Å20.0017 Å2--0.0039 Å2
L0.1247 °20.0848 °20.0161 °2-0.2197 °20.0066 °2--0.1169 °2
S-0.0003 Å °-0.0063 Å °-0.0177 Å °0.018 Å °0.0015 Å °-0.024 Å °0.0137 Å °0.014 Å °-0.0012 Å °
Refinement TLS groupSelection details: { A|* }

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