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- PDB-6mva: LDHA structure in complex with inhibitor 14 -

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Basic information

Entry
Database: PDB / ID: 6mva
TitleLDHA structure in complex with inhibitor 14
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / LDHA / inhibitor / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
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
Chem-D4S / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.02 Å
AuthorsEigenbrot, C.E. / Ultsch, M. / Wei, B.
CitationJournal: To Be Published
Title: Structure-based Optimization of Potent, Cell-Active Hydroxylactam Inhibitors of Lactate Dehydrogenase
Authors: Wei, B. / Robarge, K. / Labadie, S.S. / Chen, J. / Corson, L.B. / DiPasquale, A. / Eigenbrot, C. / Ultsch, M.
History
DepositionOct 24, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 30, 2019Provider: 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

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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)152,22717
Polymers146,9394
Non-polymers5,28913
Water11,692649
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area26660 Å2
ΔGint-189 kcal/mol
Surface area44270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.541, 81.493, 103.532
Angle α, β, γ (deg.)90.000, 98.550, 90.000
Int Tables number4
Space group name H-MP1211

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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, 662 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
#3: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-D4S / (6R)-6-(3-aminophenyl)-3-[(2-chlorophenyl)sulfanyl]-4-hydroxy-6-(thiophen-3-yl)-5,6-dihydro-2H-pyran-2-one


Mass: 429.940 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H16ClNO3S2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 649 / 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: 2.23 Å3/Da / Density % sol: 44.84 %
Crystal growTemperature: 292 K / Method: vapor diffusion / Details: 30% PEG 3350 0.1M HEPES

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Data collection

DiffractionMean temperature: 193 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 13, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.02→50 Å / Num. obs: 81874 / % possible obs: 98.9 % / Redundancy: 3.3 % / Biso Wilson estimate: 36.44 Å2 / Rmerge(I) obs: 0.095 / Χ2: 1.042 / Net I/σ(I): 10
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.05-2.123.40.61982031.003199.5
2.12-2.213.40.52881581.085199.3
2.21-2.313.30.41381371.087198.9
2.31-2.433.40.31581591.068198.9
2.43-2.583.40.22781211.051198.6
2.58-2.783.40.17481521.048198.6
2.78-3.063.30.12581501.032198.6
3.06-3.513.30.08981991.005199.1
3.51-4.423.20.06682281.024198.9
4.42-503.30.05983671.015199

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementResolution: 2.02→37.86 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.948 / Rfactor Rfree error: 0 / WRfactor Rfree: 0.3985 / WRfactor Rwork: 0.3828 / FOM work R set: 0.6005 / SU R Cruickshank DPI: 0.212 / SU Rfree: 0.2746 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.214 / SU Rfree Blow DPI: 0.156 / SU Rfree Cruickshank DPI: 0.157
RfactorNum. reflection% reflectionSelection details
Rfree0.209 1684 2.06 %RANDOM
Rwork0.19 ---
obs0.19 81736 96.4 %-
Displacement parametersBiso max: 139.79 Å2 / Biso mean: 41.19 Å2 / Biso min: 22.5 Å2
Baniso -1Baniso -2Baniso -3
1--1.2113 Å20 Å26.3272 Å2
2---0.3724 Å20 Å2
3---1.5837 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 2.02→37.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10065 0 347 649 11061
Biso mean--50.24 43.57 -
Num. residues----1300
LS refinement shellResolution: 2.02→2.07 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.237 89 2.16 %
Rwork0.217 4037 -
all0.218 4126 -
obs--66.08 %

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