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- PDB-5w8k: Crystal Structure of Lactate Dehydrogenase A in complex with inhi... -

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Basic information

Entry
Database: PDB / ID: 5w8k
TitleCrystal Structure of Lactate Dehydrogenase A in complex with inhibitor compound 29 and NADH
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE / oxidoreductase inhibitor
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-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 / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsLukacs, C.M. / Dranow, D.M.
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

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)152,88830
Polymers146,9394
Non-polymers5,94926
Water20,0331112
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area31400 Å2
ΔGint-203 kcal/mol
Surface area39480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)167.760, 81.080, 120.440
Angle α, β, γ (deg.)90.000, 117.140, 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, 1138 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.: 3 / Source method: obtained synthetically / Formula: C20H14F2N4O5S2
#3: Chemical
ChemComp-NAI / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / NADH


Mass: 665.441 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H29N7O14P2
#4: 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
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1112 / 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: 2.38 Å3/Da / Density % sol: 48 %
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: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jul 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 1.6→107.18 Å / Num. obs: 188569 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 23.56 Å2 / Rmerge(I) obs: 0.057 / Net I/σ(I): 15.65
Reflection shellResolution: 1.6→1.64 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.545 / Mean I/σ(I) obs: 2.4 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: proprietary structure of the same target

Resolution: 1.6→107.18 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.97 / SU B: 2.658 / SU ML: 0.047 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.067 / ESU R Free: 0.067
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.161 9476 5 %RANDOM
Rwork0.138 ---
obs0.139 188569 99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 67.78 Å2 / Biso mean: 17.56 Å2 / Biso min: 7.2 Å2
Baniso -1Baniso -2Baniso -3
1-0.29 Å2-0 Å2-0.11 Å2
2--0.42 Å20 Å2
3----0.39 Å2
Refinement stepCycle: final / Resolution: 1.6→107.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9941 0 394 1112 11447
Biso mean--20.96 30.19 -
Num. residues----1313
LS refinement shellResolution: 1.6→1.64 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.239 695 -
Rwork0.238 13200 -
all-13895 -
obs--99.5 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.0486-0.04240.02710.44690.27710.4771-0.00180.03730.0118-0.0366-0.0021-0.0373-0.05840.04850.00390.0391-0.01090.00120.04860.00470.048447.68591.994624.0501
20.4652-0.0042-0.00150.21690.02610.293-0.0201-0.03990.04580.02830.0148-0.0089-0.09310.00690.00530.07350.0015-0.00270.0247-0.00620.033534.783219.865538.4792
311.97531.2433-3.48192.17510.73422.50710.0704-0.26960.24320.1091-0.0415-0.0489-0.21860.0683-0.02880.13820.0005-0.02240.0123-0.0140.028139.034934.529344.8335
41.85190.4209-0.36353.93172.30523.2867-0.0357-0.1824-0.16420.4733-0.01250.18940.30230.06820.04820.08330.02550.02770.12840.01050.04267.91266.521252.005
50.3787-0.25130.17380.6799-0.15890.362-0.0013-0.0506-0.00580.04190.02250.0107-0.0114-0.0405-0.02120.0431-0.00220.00210.04610.00080.021137.5518-8.131947.7938
60.2203-0.014600.17210.08660.53050.005-0.0083-0.050.0050.004-0.02480.06120.0522-0.0090.04110.0021-0.00320.0383-0.00180.047346.502-20.372131.3348
71.5772-1.1676-1.97172.47651.6585.21-0.1047-0.0214-0.21150.253-0.02360.18640.3966-0.090.12830.0789-0.0363-0.01180.02560.01430.084531.8663-33.319726.3497
80.30210.05440.05040.22750.13680.3069-0.0036-0.04070.0007-0.00270.00440.0493-0.0151-0.0905-0.00070.01830.0140.00030.06350.01410.04455.07781.838829.2338
90.1748-0.1560.03590.2496-0.03940.25220.01750.0499-0.0184-0.0428-0.01330.02480.00210-0.00420.0389-0.0037-0.00210.05390.00120.042128.0004-5.65475.1336
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 71
2X-RAY DIFFRACTION2A72 - 309
3X-RAY DIFFRACTION3A310 - 331
4X-RAY DIFFRACTION4B1 - 15
5X-RAY DIFFRACTION5B16 - 125
6X-RAY DIFFRACTION6B126 - 330
7X-RAY DIFFRACTION7C1 - 17
8X-RAY DIFFRACTION8C18 - 331
9X-RAY DIFFRACTION9D1 - 331

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