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- PDB-6bag: Lactate Dehydrogenase in complex with inhibitor (R)-5-((2-chlorop... -

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Basic information

Entry
Database: PDB / ID: 6bag
TitleLactate Dehydrogenase in complex with inhibitor (R)-5-((2-chlorophenyl)thio)-6'-((4-fluorophenyl)amino)-4-hydroxy-2-(thiophen-3-yl)-2,3-dihydro-[2,2'-bipyridin]-6(1H)-one
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE/Inhibitor / 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-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-D0V / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsUltsch, M. / Eigenbrot, C.
CitationJournal: To Be Published
Title: Structure-guided optimization and in vivo activities of hydroxylactone and hydroxylactam Inhibitors of Human Lactate Dehydrogenase
Authors: Wei, B. / Labadie, S.S. / Robarge, K. / Chen, J. / Chen, Z. / Corson, L.B. / Ding, C.Z. / DiPasquale, A.G. / Dragovich, P.S. / Eigenbrot, C. / Evangelista, M. / Fauber, B.P. / Goa, Z. / Ge, ...Authors: Wei, B. / Labadie, S.S. / Robarge, K. / Chen, J. / Chen, Z. / Corson, L.B. / Ding, C.Z. / DiPasquale, A.G. / Dragovich, P.S. / Eigenbrot, C. / Evangelista, M. / Fauber, B.P. / Goa, Z. / Ge, H. / Hitz, A. / Ho, Q. / Lai, K.W. / Liu, W. / Liu, Y. / Li, C. / Ma, S. / Malek, S. / O'Brien, T. / Pang, J. / Peterson, D. / Salphati, L. / Sideris, S. / Ultsch, M. / Yen, I. / Yue, Q. / Zhang, H. / Zhou, A. / Purkey, H.E.
History
DepositionOct 12, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 17, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 4, 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
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)152,26319
Polymers146,4144
Non-polymers5,84915
Water7,512417
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area27660 Å2
ΔGint-230 kcal/mol
Surface area44880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.799, 81.007, 102.756
Angle α, β, γ (deg.)90.00, 98.53, 90.00
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: 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

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Non-polymers , 5 types, 432 molecules

#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-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-D0V / (2R)-5-[(2-chlorophenyl)sulfanyl]-6'-[(4-fluorophenyl)amino]-4-hydroxy-2-(thiophen-3-yl)-2,3-dihydro[2,2'-bipyridin]-6(1H)-one


Mass: 524.029 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H19ClFN3O2S2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 417 / 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: 2.22 Å3/Da / Density % sol: 44.47 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: PEG3350, sodium malonate

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Oct 31, 2012
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 50771 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 32.2 Å2 / Rsym value: 0.115 / Net I/σ(I): 11.8
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 3.7 % / Num. unique obs: 5019 / Rsym value: 0.06 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1I10

1i10


Resolution: 2.4→47.07 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.928 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.539 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.531 / SU Rfree Blow DPI: 0.233 / SU Rfree Cruickshank DPI: 0.237
RfactorNum. reflection% reflectionSelection details
Rfree0.213 1046 2.06 %RANDOM
Rwork0.175 ---
obs0.176 50707 99.7 %-
Displacement parametersBiso mean: 36.67 Å2
Baniso -1Baniso -2Baniso -3
1-1.2886 Å20 Å24.7084 Å2
2---2.3873 Å20 Å2
3---1.0986 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: 1 / Resolution: 2.4→47.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10183 0 381 417 10981
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00910820HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0714697HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4062SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes251HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1515HARMONIC5
X-RAY DIFFRACTIONt_it10820HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.93
X-RAY DIFFRACTIONt_other_torsion17.47
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1403SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact12493SEMIHARMONIC4
LS refinement shellResolution: 2.39→2.45 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.261 -1.84 %
Rwork0.215 3578 -
all0.216 3645 -
obs--97.1 %

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