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- PDB-5w8j: Crystal Structure of Lactate Dehydrogenase A in complex with inhi... -

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Basic information

Entry
Database: PDB / ID: 5w8j
TitleCrystal Structure of Lactate Dehydrogenase A in complex with inhibitor compound 29
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE / oxidoreductase inhibitor
Function / homology
Function and homology information


L-lactate dehydrogenase / oxidoreductase complex / Pyruvate metabolism / lactate metabolic process / L-lactate dehydrogenase activity / pyruvate metabolic process / substantia nigra development / Regulation of pyruvate metabolism / glycolytic process / cadherin binding ...L-lactate dehydrogenase / oxidoreductase complex / Pyruvate metabolism / lactate metabolic process / L-lactate dehydrogenase activity / pyruvate metabolic process / substantia nigra development / Regulation of pyruvate metabolism / 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-2-Hydroxyisocaproate Dehydrogenase; Chain A, domain 2 / Lactate dehydrogenase/glycoside hydrolase, family 4, C-terminal / 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 ...L-lactate dehydrogenase / L-lactate dehydrogenase active site. / L-lactate dehydrogenase, active site / L-2-Hydroxyisocaproate Dehydrogenase; Chain A, domain 2 / Lactate dehydrogenase/glycoside hydrolase, family 4, C-terminal / 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 Rossmann-like Domain / NAD(P)-binding domain superfamily / Alpha-Beta Complex / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-9Y7 / MALONIC ACID / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsLukacs, C.M. / Moulin, A.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH).
Authors: Rai, G. / Brimacombe, K.R. / Mott, B.T. / Urban, D.J. / Hu, X. / Yang, S.M. / Lee, T.D. / Cheff, D.M. / Kouznetsova, J. / Benavides, G.A. / Pohida, K. / Kuenstner, E.J. / Luci, D.K. / ...Authors: Rai, G. / Brimacombe, K.R. / Mott, B.T. / Urban, D.J. / Hu, X. / Yang, S.M. / Lee, T.D. / Cheff, D.M. / Kouznetsova, J. / Benavides, G.A. / Pohida, K. / Kuenstner, E.J. / Luci, D.K. / Lukacs, C.M. / Davies, D.R. / Dranow, D.M. / Zhu, H. / Sulikowski, G. / Moore, W.J. / Stott, G.M. / Flint, A.J. / Hall, M.D. / Darley-Usmar, V.M. / Neckers, L.M. / Dang, C.V. / Waterson, A.G. / Simeonov, A. / Jadhav, A. / Maloney, D.J.
History
DepositionJun 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 17, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)150,98922
Polymers146,9394
Non-polymers4,05018
Water23,9241328
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area24330 Å2
ΔGint-160 kcal/mol
Surface area42270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)168.530, 80.770, 121.090
Angle α, β, γ (deg.)90.000, 118.230, 90.000
Int Tables number5
Space group name H-MC121

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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: 36734.672 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 , 5 types, 1346 molecules

#2: Chemical
ChemComp-9Y7 / 2-{3-(3,4-difluorophenyl)-5-hydroxy-4-[(4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid


Mass: 492.476 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C20H14F2N4O5S2
#3: Chemical
ChemComp-MLA / MALONIC ACID / DICARBOXYLIC ACID C3 / PROPANEDIOLIC ACID / METHANEDICARBOXYLIC ACID


Mass: 104.061 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H4O4
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1328 / Source method: isolated from a natural source / Formula: H2O

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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: 2.34 Å3/Da / Density % sol: 47 %
Crystal growTemperature: 289 K / Method: vapor diffusion / pH: 6.8
Details: 24% PEG 3350, 200 mM Sodium Malonate, pH 6.8, 10% Glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97949 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 6, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.55→50 Å / Num. obs: 217276 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 4.16 % / Biso Wilson estimate: 22.93 Å2 / Rmerge(I) obs: 0.067 / Net I/σ(I): 12.85
Reflection shellResolution: 1.55→1.59 Å / Redundancy: 4.15 % / Rmerge(I) obs: 0.498 / Mean I/σ(I) obs: 3.2 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: proprietary structure of the same target

Resolution: 1.55→46.12 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflectionSelection details
Rfree0.169 10414 5.03 %RANDOM
Rwork0.145 ---
obs0.146 217276 99.7 %-
Displacement parametersBiso max: 61.66 Å2 / Biso mean: 19.36 Å2 / Biso min: 6.4 Å2
Refinement stepCycle: final / Resolution: 1.55→46.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10081 0 265 1328 11674
Biso mean--26.3 30.39 -
Num. residues----1322
LS refinement shellResolution: 1.55→1.57 Å / Rfactor Rfree error: 0 / Total num. of bins used: 30
RfactorNum. reflection% reflection
Rfree0.221 357 -
Rwork0.193 6529 -
all-6886 -
obs--100 %

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