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- PDB-7m2n: Crystal structure of Human Lactate Dehydrogenase A with Inhibitor... -

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Basic information

Entry
Database: PDB / ID: 7m2n
TitleCrystal structure of Human Lactate Dehydrogenase A with Inhibitor Compound 15
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE
Function / homology
Function and homology information


oxidoreductase complex / Pyruvate metabolism / L-lactate dehydrogenase / lactate metabolic process / L-lactate dehydrogenase activity / pyruvate metabolic process / substantia nigra development / glycolytic process / cadherin binding / mitochondrion ...oxidoreductase complex / Pyruvate metabolism / L-lactate dehydrogenase / lactate metabolic process / L-lactate dehydrogenase activity / pyruvate metabolic process / substantia nigra development / glycolytic process / cadherin binding / mitochondrion / extracellular exosome / identical protein binding / membrane / nucleus / cytosol
Similarity search - Function
L-lactate dehydrogenase / L-lactate dehydrogenase active site. / L-lactate dehydrogenase, active site / L-lactate/malate dehydrogenase / Lactate/malate dehydrogenase, N-terminal / Lactate/malate dehydrogenase, C-terminal / lactate/malate dehydrogenase, NAD binding domain / lactate/malate dehydrogenase, alpha/beta C-terminal domain / Lactate dehydrogenase/glycoside hydrolase, family 4, C-terminal / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / DI(HYDROXYETHYL)ETHER / Chem-YOJ / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsGumpena, R. / Ding, J. / Powell, D.A. / Lowther, W.T.
CitationJournal: ACS Medicinal Chemistry Letters / Year: 2021
Title: Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria
Authors: Ding, J. / Gumpena, R. / Boily, M.O. / Caron, A. / Chong, O. / Cox, J.H. / Dumais, V. / Gaudreault, S. / Graff, A.H. / King, A. / Knight, J. / Oballa, R. / Surendradoss, J. / Tang, T. / Wu, ...Authors: Ding, J. / Gumpena, R. / Boily, M.O. / Caron, A. / Chong, O. / Cox, J.H. / Dumais, V. / Gaudreault, S. / Graff, A.H. / King, A. / Knight, J. / Oballa, R. / Surendradoss, J. / Tang, T. / Wu, J. / Lowther, W.T. / Powell, D.A.
History
DepositionMar 17, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 14, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: L-lactate dehydrogenase A chain
B: L-lactate dehydrogenase A chain
C: L-lactate dehydrogenase A chain
D: L-lactate dehydrogenase A chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)162,656109
Polymers150,2544
Non-polymers12,402105
Water9,674537
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)83.930, 131.050, 215.518
Angle α, β, γ (deg.)90.00, 99.30, 90.00
Int Tables number5
Space group name H-MI121
Components on special symmetry positions
IDModelComponents
11D-423-

SO4

21D-534-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: PHE / End label comp-ID: PHE / Refine code: _ / Auth seq-ID: 1 - 331 / Label seq-ID: 2 - 332

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
L-lactate dehydrogenase A chain / LDH-A / Cell proliferation-inducing gene 19 protein / LDH muscle subunit / LDH-M / Renal carcinoma ...LDH-A / Cell proliferation-inducing gene 19 protein / LDH muscle subunit / LDH-M / Renal carcinoma antigen NY-REN-59


Mass: 37563.543 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LDHA, PIG19 / Production host: Escherichia coli (E. coli) / References: UniProt: P00338, L-lactate dehydrogenase

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Non-polymers , 7 types, 642 molecules

#2: Chemical
ChemComp-NAI / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / NADH


Mass: 665.441 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H29N7O14P2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#4: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 75 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C4H10O3
#7: Chemical
ChemComp-YOJ / 5-[(5'-{1-(4-carboxy-1,3-thiazol-2-yl)-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-1H-pyrazol-3-yl}-2'-fluoro[1,1'-biphenyl]-4-yl)oxy]-1H-1,2,3-triazole-4-carboxylic acid


Mass: 733.721 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H25F2N7O7S2 / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 537 / 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: 4.01 Å3/Da / Density % sol: 69.31 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Lithium Sulfate, 0.1 M Sodium Cacodylate pH 6.5, 30% (v/v) PEG 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Nov 5, 2019
RadiationMonochromator: Cu / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 78979 / % possible obs: 100 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.104 / Net I/σ(I): 13.46
Reflection shellResolution: 2.5→2.54 Å / Num. unique obs: 3992 / CC1/2: 0.87

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
HKL-3000data reduction
HKL-3000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5W8J

5w8j


Resolution: 2.5→48.89 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.9 / SU B: 7.979 / SU ML: 0.179 / Cross valid method: THROUGHOUT / ESU R: 0.341 / ESU R Free: 0.259 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25769 3910 5 %RANDOM
Rwork0.20938 ---
obs0.21175 74825 97.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.906 Å2
Baniso -1Baniso -2Baniso -3
1--0 Å20 Å2-0.01 Å2
2---0 Å20 Å2
3---0.01 Å2
Refinement stepCycle: 1 / Resolution: 2.5→48.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10170 0 808 537 11515
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01311174
X-RAY DIFFRACTIONr_bond_other_d0.0010.01710933
X-RAY DIFFRACTIONr_angle_refined_deg1.4611.68115027
X-RAY DIFFRACTIONr_angle_other_deg1.2311.59525154
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.58851319
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.77823.454443
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.5151903
X-RAY DIFFRACTIONr_dihedral_angle_4_deg25.2071544
X-RAY DIFFRACTIONr_chiral_restr0.0720.21412
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211968
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022257
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9363.6755280
X-RAY DIFFRACTIONr_mcbond_other2.9353.6755279
X-RAY DIFFRACTIONr_mcangle_it4.3135.5056591
X-RAY DIFFRACTIONr_mcangle_other4.3135.5066592
X-RAY DIFFRACTIONr_scbond_it3.6694.2935894
X-RAY DIFFRACTIONr_scbond_other3.6694.2945895
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.5856.1828419
X-RAY DIFFRACTIONr_long_range_B_refined7.55644.07712055
X-RAY DIFFRACTIONr_long_range_B_other7.55944.05512042
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A101130.06
12B101130.06
21A100380.07
22C100380.07
31A101400.06
32D101400.06
41B101060.06
42C101060.06
51B102110.06
52D102110.06
61C101800.06
62D101800.06
LS refinement shellResolution: 2.5→2.553 Å
RfactorNum. reflection% reflection
Rfree0.313 213 -
Rwork0.258 4086 -
obs--72.14 %

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