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- PDB-4r69: Lactate Dehydrogenase in complex with inhibitor compound 13 -

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Basic information

Entry
Database: PDB / ID: 4r69
TitleLactate Dehydrogenase in complex with inhibitor compound 13
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE
Function / homology
Function and homology information


oxidoreductase complex / L-lactate dehydrogenase / Pyruvate metabolism / lactate metabolic process / L-lactate dehydrogenase activity / pyruvate metabolic process / substantia nigra development / Regulation of pyruvate metabolism / glycolytic process / cadherin binding ...oxidoreductase complex / L-lactate dehydrogenase / 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
1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / Chem-W13 / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.19 Å
AuthorsEigenbrot, C. / Ultsch, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.
Authors: Labadie, S. / Dragovich, P.S. / Chen, J. / Fauber, B.P. / Boggs, J. / Corson, L.B. / Ding, C.Z. / Eigenbrot, C. / Ge, H. / Ho, Q. / Lai, K.W. / Ma, S. / Malek, S. / Peterson, D. / Purkey, H. ...Authors: Labadie, S. / Dragovich, P.S. / Chen, J. / Fauber, B.P. / Boggs, J. / Corson, L.B. / Ding, C.Z. / Eigenbrot, C. / Ge, H. / Ho, Q. / Lai, K.W. / Ma, S. / Malek, S. / Peterson, D. / Purkey, H.E. / Robarge, K. / Salphati, L. / Sideris, S. / Ultsch, M. / VanderPorten, E. / Wei, B. / Xu, Q. / Yen, I. / Yue, Q. / Zhang, H. / Zhang, X. / Zhou, A.
History
DepositionAug 22, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 24, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_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)151,88216
Polymers146,4144
Non-polymers5,46812
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area27050 Å2
ΔGint-178 kcal/mol
Surface area42420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.007, 80.682, 101.983
Angle α, β, γ (deg.)90.00, 96.49, 90.00
Int Tables number4
Space group name H-MP1211
Detailsthe crystallographic asymmetric unit contains the biological assembly, a homotetramer

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Components

#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: 36603.473 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
#2: 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
#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-W13 / (5R)-2-[(2-chlorophenyl)sulfanyl]-5-[2,6-dichloro-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]-3-hydroxycyclohex-2-en-1-one


Mass: 498.850 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H22Cl3NO3S
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4

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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: 2.09 Å3/Da / Density % sol: 41.26 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: PEG3350, pH 7.2, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: May 8, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 3.19→38.9 Å / Num. all: 20265 / Num. obs: 20264 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 46.8 Å2 / Rsym value: 0.214 / Net I/σ(I): 6.3

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
BUSTER2.11.4refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4M49
Resolution: 3.19→38.83 Å / Cor.coef. Fo:Fc: 0.9013 / Cor.coef. Fo:Fc free: 0.8677 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2278 451 2.23 %RANDOM
Rwork0.1896 ---
all0.191 20265 --
obs0.1905 20264 99.49 %-
Displacement parametersBiso mean: 42.21 Å2
Baniso -1Baniso -2Baniso -3
1-1.2075 Å20 Å26.7201 Å2
2---1.7501 Å20 Å2
3---0.5426 Å2
Refine analyzeLuzzati coordinate error obs: 0.506 Å
Refinement stepCycle: LAST / Resolution: 3.19→38.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10076 0 350 0 10426
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00810696HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0714527HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d18.93849SINUSOIDAL2
X-RAY DIFFRACTIONt_omega_torsion2.19
X-RAY DIFFRACTIONt_other_torsion18.92
LS refinement shellResolution: 3.19→3.36 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2288 72 2.52 %
Rwork0.2214 2789 -
all0.2216 2861 -
obs--99.49 %

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