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- PDB-6bb0: Lactate Dehydrogenase in complex with inhibitor (R)-3-((2-chlorop... -

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Basic information

Entry
Database: PDB / ID: 6bb0
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 / OXIDOREDUCTASE-Inhibitor complex
Function / homology
Function and homology information


sperm fibrous sheath / pyruvate catabolic process / L-lactate dehydrogenase / oxidoreductase complex / pyruvate metabolic process / L-lactate dehydrogenase (NAD+) activity / Pyruvate metabolism / lactate metabolic process / glucose catabolic process to lactate via pyruvate / substantia nigra development ...sperm fibrous sheath / pyruvate catabolic process / L-lactate dehydrogenase / oxidoreductase complex / pyruvate metabolic process / L-lactate dehydrogenase (NAD+) activity / Pyruvate metabolism / lactate metabolic process / glucose catabolic process to lactate via pyruvate / substantia nigra development / Regulation of pyruvate metabolism / glycolytic process / cadherin binding / mitochondrion / extracellular exosome / identical protein binding / nucleus / membrane / 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-D3S / LACTIC ACID / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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 16, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 24, 2018Provider: repository / Type: Initial release
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Database references
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _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)151,53219
Polymers146,4144
Non-polymers5,11815
Water12,989721
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area27360 Å2
ΔGint-238 kcal/mol
Surface area43290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.125, 80.968, 103.214
Angle α, β, γ (deg.)90.00, 98.33, 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 , 6 types, 736 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.: 3 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-D3S / (6S)-3-[(2-chlorophenyl)sulfanyl]-4-hydroxy-6-(2-hydroxyphenyl)-6-phenyl-5,6-dihydro-2H-pyran-2-one


Mass: 424.897 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C23H17ClO4S
#6: Chemical ChemComp-LAC / LACTIC ACID


Mass: 90.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H6O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 721 / 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: 2.21 Å3/Da / Density % sol: 44.25 %
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: SSRL / Beamline: BL11-1 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 12, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.95→39 Å / Num. obs: 91115 / % possible obs: 97.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.4 % / Biso Wilson estimate: 31 Å2 / Rsym value: 0.046 / Net I/σ(I): 16.6
Reflection shellResolution: 1.95→2.05 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 2.3 / Num. unique obs: 13021 / Rsym value: 0.491 / % possible all: 95.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→38.65 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.951 / SU B: 4.441 / SU ML: 0.122 / Cross valid method: THROUGHOUT / ESU R: 0.165 / ESU R Free: 0.151 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21507 1830 2 %RANDOM
Rwork0.16648 ---
obs0.16753 89141 97.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso mean: 37.916 Å2
Baniso -1Baniso -2Baniso -3
1--1.27 Å20 Å2-1.47 Å2
2--2.2 Å2-0 Å2
3----0.48 Å2
Refinement stepCycle: 1 / Resolution: 1.95→38.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10065 0 334 721 11120
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.01910670
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210491
X-RAY DIFFRACTIONr_angle_refined_deg1.5092.0114492
X-RAY DIFFRACTIONr_angle_other_deg0.976324212
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.71351315
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.65325.089395
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.758151935
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.2111541
X-RAY DIFFRACTIONr_chiral_restr0.1720.21697
X-RAY DIFFRACTIONr_gen_planes_refined0.0210.0211607
X-RAY DIFFRACTIONr_gen_planes_other0.0170.022175
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it8.6455.475218
X-RAY DIFFRACTIONr_mcbond_other8.5985.4685217
X-RAY DIFFRACTIONr_mcangle_it9.32512.1766517
X-RAY DIFFRACTIONr_mcangle_other9.33112.186518
X-RAY DIFFRACTIONr_scbond_it12.8116.7945452
X-RAY DIFFRACTIONr_scbond_other12.8336.7745389
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other14.20914.3697874
X-RAY DIFFRACTIONr_long_range_B_refined13.92440.22312243
X-RAY DIFFRACTIONr_long_range_B_other13.94540.09812141
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.95→2.055 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.307 260 -
Rwork0.253 12962 -
obs--97.96 %

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