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- PDB-7fs2: Structure of liver pyruvate kinase in complex with allosteric mod... -

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Basic information

Entry
Database: PDB / ID: 7fs2
TitleStructure of liver pyruvate kinase in complex with allosteric modulator 13
ComponentsPyruvate kinase PKLR
KeywordsTRANSFERASE / Pyruvate kinase / active site / inhibition
Function / homology
Function and homology information


pyruvate kinase complex / pyruvate biosynthetic process / SARS-CoV-1-host interactions / ChREBP activates metabolic gene expression / pyruvate kinase / pyruvate kinase activity / response to metal ion / monosaccharide binding / Glycolysis / response to ATP ...pyruvate kinase complex / pyruvate biosynthetic process / SARS-CoV-1-host interactions / ChREBP activates metabolic gene expression / pyruvate kinase / pyruvate kinase activity / response to metal ion / monosaccharide binding / Glycolysis / response to ATP / potassium ion binding / Regulation of gene expression in beta cells / response to glucose / response to cAMP / cellular response to epinephrine stimulus / response to nutrient / glycolytic process / cellular response to insulin stimulus / kinase activity / response to hypoxia / phosphorylation / magnesium ion binding / extracellular exosome / ATP binding / cytosol / cytoplasm
Similarity search - Function
Pyruvate kinase, active site / Pyruvate kinase active site signature. / Pyruvate kinase / Pyruvate kinase, barrel / Pyruvate kinase, insert domain superfamily / Pyruvate kinase, barrel domain / Pyruvate kinase, C-terminal / Pyruvate kinase, C-terminal domain superfamily / Pyruvate kinase, alpha/beta domain / Pyruvate kinase-like, insert domain superfamily ...Pyruvate kinase, active site / Pyruvate kinase active site signature. / Pyruvate kinase / Pyruvate kinase, barrel / Pyruvate kinase, insert domain superfamily / Pyruvate kinase, barrel domain / Pyruvate kinase, C-terminal / Pyruvate kinase, C-terminal domain superfamily / Pyruvate kinase, alpha/beta domain / Pyruvate kinase-like, insert domain superfamily / Pyruvate kinase-like domain superfamily / Pyruvate/Phosphoenolpyruvate kinase-like domain superfamily
Similarity search - Domain/homology
1,6-di-O-phosphono-beta-D-fructofuranose / : / Chem-O7X / OXALATE ION / Pyruvate kinase PKLR
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.374 Å
AuthorsLulla, A. / Nilsson, O. / Brear, P. / Nain-Perez, A. / Grotli, M. / Hyvonen, M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Not funded United Kingdom
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Tuning liver pyruvate kinase activity up or down with a new class of allosteric modulators.
Authors: Nain-Perez, A. / Nilsson, O. / Lulla, A. / Haversen, L. / Brear, P. / Liljenberg, S. / Hyvonen, M. / Boren, J. / Grotli, M.
History
DepositionDec 18, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 12, 2023Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Pyruvate kinase PKLR
B: Pyruvate kinase PKLR
C: Pyruvate kinase PKLR
D: Pyruvate kinase PKLR
E: Pyruvate kinase PKLR
F: Pyruvate kinase PKLR
G: Pyruvate kinase PKLR
H: Pyruvate kinase PKLR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)392,39044
Polymers386,2838
Non-polymers6,10736
Water17,727984
1
A: Pyruvate kinase PKLR
B: Pyruvate kinase PKLR
C: Pyruvate kinase PKLR
D: Pyruvate kinase PKLR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,19522
Polymers193,1424
Non-polymers3,05318
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area22570 Å2
ΔGint-133 kcal/mol
Surface area56380 Å2
MethodPISA
2
E: Pyruvate kinase PKLR
F: Pyruvate kinase PKLR
G: Pyruvate kinase PKLR
H: Pyruvate kinase PKLR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,19522
Polymers193,1424
Non-polymers3,05318
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area22560 Å2
ΔGint-131 kcal/mol
Surface area55430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)207.669, 113.013, 187.767
Angle α, β, γ (deg.)90.000, 92.410, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein / Sugars , 2 types, 16 molecules ABCDEFGH

#1: Protein
Pyruvate kinase PKLR / / Pyruvate kinase 1 / Pyruvate kinase isozymes L/R / R-type/L-type pyruvate kinase / Red cell/liver ...Pyruvate kinase 1 / Pyruvate kinase isozymes L/R / R-type/L-type pyruvate kinase / Red cell/liver pyruvate kinase


Mass: 48285.379 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PKLR, PK1, PKL / Plasmid: pEXP-NHis / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P30613, pyruvate kinase
#2: Sugar
ChemComp-FBP / 1,6-di-O-phosphono-beta-D-fructofuranose / BETA-FRUCTOSE-1,6-DIPHOSPHATE / FRUCTOSE-1,6-BISPHOSPHATE / 1,6-di-O-phosphono-beta-D-fructose / 1,6-di-O-phosphono-D-fructose / 1,6-di-O-phosphono-fructose / Fructose 1,6-bisphosphate


Type: D-saccharide, beta linking / Mass: 340.116 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C6H14O12P2
IdentifierTypeProgram
b-D-Fruf1PO36PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0

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Non-polymers , 5 types, 1012 molecules

#3: Chemical
ChemComp-OXL / OXALATE ION / Oxalate


Mass: 88.019 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2O4
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Mg
#5: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: K
#6: Chemical
ChemComp-O7X / (1P)-3',4,4',5-tetrahydroxy-N-{[4-(3-hydroxybenzene-1-sulfonyl)phenyl]methyl}[1,1'-biphenyl]-2-sulfonamide


Mass: 543.566 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H21NO9S2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 984 / 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: 2.85 Å3/Da / Density % sol: 56.83 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100 mM HEPES/MOPS, 10% PEG8000, 20% ethylene glycol, 10 mM phenylalanine, 20 mM sodium oxalate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Oct 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.374→103.743 Å / Num. obs: 118487 / % possible obs: 92.7 % / Redundancy: 11.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.216 / Rpim(I) all: 0.066 / Net I/σ(I): 9.2 / Num. measured all: 1377909
Reflection shell
Resolution (Å)% possible obs (%)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique obsCC1/2Rpim(I) all
2.374-2.59960.311.81.8661.56989059250.580.565
7.405-103.74399.511.50.05126.86805859220.9990.016

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
PHASERphasing
BUSTER2.10.4 (16-JUL-2021)refinement
PDB_EXTRACT3.25data extraction
STARANISOdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.374→187.6 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.918 / SU R Cruickshank DPI: 0.989 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.914 / SU Rfree Blow DPI: 0.304 / SU Rfree Cruickshank DPI: 0.31
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2395 6074 5.13 %RANDOM
Rwork0.2033 ---
obs0.2051 118488 67.7 %-
Displacement parametersBiso max: 125.39 Å2 / Biso mean: 51.41 Å2 / Biso min: 12.13 Å2
Baniso -1Baniso -2Baniso -3
1--0.3079 Å20 Å2-0.4512 Å2
2---0.8152 Å20 Å2
3---1.1231 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.374→187.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms25843 0 372 984 27199
Biso mean--54.26 44.74 -
Num. residues----3405
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d9599SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes4845HARMONIC5
X-RAY DIFFRACTIONt_it26914HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion3608SEMIHARMONIC5
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_contact22875SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d26998HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg36679HARMONIC20.91
X-RAY DIFFRACTIONt_omega_torsion2.78
X-RAY DIFFRACTIONt_other_torsion17.18
LS refinement shellResolution: 2.37→2.52 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3387 113 4.77 %
Rwork0.2813 2257 -
all0.2843 2370 -
obs--8.37 %

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