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- PDB-7bhv: Crystal structure of MAT2a bound to allosteric inhibitor and in v... -

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Basic information

Entry
Database: PDB / ID: 7bhv
TitleCrystal structure of MAT2a bound to allosteric inhibitor and in vivo tool compound 28
ComponentsS-adenosylmethionine synthase isoform type-2
KeywordsTRANSFERASE / allosteric inhibitor / fragment-based drug design / synthetic lethal therapy / oncology
Function / homology
Function and homology information


methionine adenosyltransferase complex / methionine adenosyltransferase / methionine adenosyltransferase activity / S-adenosylmethionine biosynthetic process / protein heterooligomerization / Methylation / 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 / protein heterooligomerization / Methylation / protein hexamerization / small molecule binding / cellular response to leukemia inhibitory factor / one-carbon metabolic process / ATP binding / metal ion binding / identical protein 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-TQB / S-adenosylmethionine synthase isoform type-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.16 Å
AuthorsSchimpl, M. / De Fusco, C. / Borjesson, U. / Cheung, T. / Collie, I. / Evans, L. / Narasimhan, P. / Stubbs, C. / Vazquez-Chantada, M. / Wagner, D.J. ...Schimpl, M. / De Fusco, C. / Borjesson, U. / Cheung, T. / Collie, I. / Evans, L. / Narasimhan, P. / Stubbs, C. / Vazquez-Chantada, M. / Wagner, D.J. / Grondine, M. / Tentarelli, S. / Underwood, E. / Argyrou, A. / Bagal, S. / Chiarparin, E. / Robb, G. / Scott, J.S.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model.
Authors: De Fusco, C. / Schimpl, M. / Borjesson, U. / Cheung, T. / Collie, I. / Evans, L. / Narasimhan, P. / Stubbs, C. / Vazquez-Chantada, M. / Wagner, D.J. / Grondine, M. / Sanders, M.G. / ...Authors: De Fusco, C. / Schimpl, M. / Borjesson, U. / Cheung, T. / Collie, I. / Evans, L. / Narasimhan, P. / Stubbs, C. / Vazquez-Chantada, M. / Wagner, D.J. / Grondine, M. / Sanders, M.G. / Tentarelli, S. / Underwood, E. / Argyrou, A. / Smith, J.M. / Lynch, J.T. / Chiarparin, E. / Robb, G. / Bagal, S.K. / Scott, J.S.
History
DepositionJan 11, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 21, 2021Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 9, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)44,6343
Polymers43,9361
Non-polymers6982
Water7,656425
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)89,2686
Polymers87,8722
Non-polymers1,3964
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_665-x+1,-y+1,z1
Buried area6630 Å2
ΔGint-27 kcal/mol
Surface area24090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.176, 93.853, 117.069
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-505-

HOH

21A-632-

HOH

31A-812-

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 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): BL21 Gold (DE3) / References: UniProt: P31153, methionine adenosyltransferase
#2: Chemical ChemComp-TQB / 7-chloranyl-4-(dimethylamino)-1-phenyl-quinazolin-2-one


Mass: 299.755 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H14ClN3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE / S-Adenosyl methionine


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


Mass: 18.015 Da / Num. of mol.: 425 / 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: 42.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8
Details: 8-12 % PEG8000, 8-12 % ethylene glycol, 0.1 M HEPES pH 8.0; soaked with 0.01 M compound (10 % DMSO)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 26, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.16→73.226 Å / Num. obs: 118866 / % possible obs: 92.2 % / Redundancy: 5.6 % / Biso Wilson estimate: 9.36 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.032 / Rpim(I) all: 0.014 / Rrim(I) all: 0.035 / Net I/σ(I): 27.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.16-1.1982.10.1151256459430.980.0950.154.650.4
3.253-73.2266.10.0263613759420.9990.0120.0295896.3

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Processing

Software
NameVersionClassification
XDSdata reduction
STARANISOdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 1.16→16.93 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.97 / SU R Cruickshank DPI: 0.032 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.034 / SU Rfree Blow DPI: 0.033 / SU Rfree Cruickshank DPI: 0.032
RfactorNum. reflection% reflectionSelection details
Rfree0.157 5930 4.99 %RANDOM
Rwork0.149 ---
obs0.149 118866 91.9 %-
Displacement parametersBiso max: 63 Å2 / Biso mean: 12.8 Å2 / Biso min: 6.21 Å2
Baniso -1Baniso -2Baniso -3
1-0.1436 Å20 Å20 Å2
2---0.0108 Å20 Å2
3----0.1327 Å2
Refine analyzeLuzzati coordinate error obs: 0.11 Å
Refinement stepCycle: final / Resolution: 1.16→16.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2923 0 48 425 3396
Biso mean--9.19 24.15 -
Num. residues----380
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1067SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes526HARMONIC5
X-RAY DIFFRACTIONt_it3066HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion397SEMIHARMONIC5
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_contact4102SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3066HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4166HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion5.52
X-RAY DIFFRACTIONt_other_torsion14.63
LS refinement shellResolution: 1.16→1.18 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.178 105 4.42 %
Rwork0.1569 2273 -
all0.1578 2378 -
obs--43.26 %
Refinement TLS params.Method: refined / Origin x: 26.1236 Å / Origin y: 38.7306 Å / Origin z: 32.6235 Å
111213212223313233
T-0.0024 Å2-0.0045 Å2-0.0042 Å2--0.0009 Å2-0.0013 Å2---0.0034 Å2
L0.135 °2-0.0529 °20.0216 °2-0.2372 °20.0032 °2--0.1117 °2
S-0.003 Å °0.0085 Å °-0.0238 Å °-0.0232 Å °0.0084 Å °0.0306 Å °0.0144 Å °-0.0154 Å °-0.0055 Å °
Refinement TLS groupSelection details: { A|* }

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