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- PDB-6bad: Lactate Dehydrogenase in complex with inhibitor (R)-3-((2-chlorop... -

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Basic information

Entry
Database: PDB / ID: 6bad
TitleLactate Dehydrogenase in complex with inhibitor (R)-3-((2-chlorophenyl)thio)-6-(3-((4-fluorophenyl)amino)phenyl)-4-hydroxy-6-(thiophen-3-yl)-5,6-dihydro-2H-pyran-2-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-D0Y / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 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)153,31224
Polymers146,4144
Non-polymers6,89820
Water13,529751
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area29110 Å2
ΔGint-238 kcal/mol
Surface area44360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.401, 80.714, 102.429
Angle α, β, γ (deg.)90.00, 96.81, 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, 771 molecules

#2: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#3: Chemical
ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-D0Y / (6R)-3-[(2-chlorophenyl)sulfanyl]-6-{3-[(4-fluorophenyl)amino]phenyl}-4-hydroxy-6-(thiophen-3-yl)-5,6-dihydro-2H-pyran-2-one


Mass: 524.026 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H19ClFNO3S2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 751 / 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: 2.11 Å3/Da / Density % sol: 41.81 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: PEG 3350, sodium malonate

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 18, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 71475 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Biso Wilson estimate: 20.1 Å2 / Rsym value: 0.109 / Net I/σ(I): 11
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 3.6 % / Mean I/σ(I) obs: 3.2 / Num. unique obs: 7188 / Rsym value: 0.412 / % possible all: 99.8

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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: 2.1→46.64 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.913 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.274 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.283 / SU Rfree Blow DPI: 0.193 / SU Rfree Cruickshank DPI: 0.193
RfactorNum. reflection% reflectionSelection details
Rfree0.23 1444 2.03 %RANDOM
Rwork0.194 ---
obs0.194 69758 97.3 %-
Displacement parametersBiso mean: 25.44 Å2
Baniso -1Baniso -2Baniso -3
1--4.8263 Å20 Å22.9667 Å2
2--1.8426 Å20 Å2
3---2.9837 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: 1 / Resolution: 2.1→46.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10268 0 446 751 11465
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110990HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0814926HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4161SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes256HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1534HARMONIC5
X-RAY DIFFRACTIONt_it10990HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.14
X-RAY DIFFRACTIONt_other_torsion17.3
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1414SEMIHARMONIC5
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_contact13342SEMIHARMONIC4
LS refinement shellResolution: 2.1→2.13 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 -2.02 %
Rwork0.286 3840 -
all0.287 3919 -
obs--72.41 %

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