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- PDB-6bb2: Lactate Dehydrogenase in complex with inhibitor (S)-5-((2-chlorop... -

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Basic information

Entry
Database: PDB / ID: 6bb2
TitleLactate Dehydrogenase in complex with inhibitor (S)-5-((2-chlorophenyl)thio)-6'-(4-fluorophenoxy)-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


sperm fibrous sheath / pyruvate catabolic process / L-lactate dehydrogenase / oxidoreductase complex / L-lactate dehydrogenase (NAD+) activity / pyruvate metabolic process / 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 / L-lactate dehydrogenase (NAD+) activity / pyruvate metabolic process / 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-D4J / LACTIC ACID / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.47 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 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
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Category: atom_site / chem_comp_atom / chem_comp_bond
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2

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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
E: L-lactate dehydrogenase A chain
F: L-lactate dehydrogenase A chain
G: L-lactate dehydrogenase A chain
H: L-lactate dehydrogenase A chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)300,73730
Polymers292,8288
Non-polymers7,90922
Water10,737596
1
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)150,34317
Polymers146,4144
Non-polymers3,92913
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area26840 Å2
ΔGint-254 kcal/mol
Surface area42420 Å2
MethodPISA
2
E: L-lactate dehydrogenase A chain
F: L-lactate dehydrogenase A chain
G: L-lactate dehydrogenase A chain
H: L-lactate dehydrogenase A chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,39413
Polymers146,4144
Non-polymers3,9809
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area26150 Å2
ΔGint-192 kcal/mol
Surface area43440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.183, 158.561, 264.978
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 8 molecules ABCDEFGH

#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.: 8
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, 618 molecules

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


Mass: 663.425 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-LAC / LACTIC ACID


Mass: 90.078 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H6O3
#5: Chemical ChemComp-D4J / (2S)-5-[(2-chlorophenyl)sulfanyl]-6'-(4-fluorophenoxy)-4-hydroxy-2-(thiophen-3-yl)-2,3-dihydro[2,2'-bipyridin]-6(1H)-one


Mass: 525.014 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C26H18ClFN2O3S2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 596 / 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: 2.34 Å3/Da / Density % sol: 47.39 %
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: Jan 25, 2013
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.47→50 Å / Num. obs: 90892 / % possible obs: 91.54 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 4.8 % / Biso Wilson estimate: 30.8 Å2 / Rsym value: 0.129 / Net I/σ(I): 10.1
Reflection shellResolution: 2.47→2.56 Å / Redundancy: 3.8 % / Mean I/σ(I) obs: 2 / Num. unique obs: 8990 / Rsym value: 0.677 / % possible all: 91.04

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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: 2.47→49.79 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.88 / SU R Cruickshank DPI: 0.968 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.056 / SU Rfree Blow DPI: 0.287 / SU Rfree Cruickshank DPI: 0.291
RfactorNum. reflection% reflectionSelection details
Rfree0.236 909 1 %RANDOM
Rwork0.19 ---
obs0.19 90891 91.3 %-
Displacement parametersBiso mean: 38.12 Å2
Baniso -1Baniso -2Baniso -3
1-0.5417 Å20 Å20 Å2
2---6.349 Å20 Å2
3---5.8073 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: 1 / Resolution: 2.47→49.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms20283 0 517 596 21396
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0121176HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1828719HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d7938SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes493HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2957HARMONIC5
X-RAY DIFFRACTIONt_it21176HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.97
X-RAY DIFFRACTIONt_other_torsion19.34
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion2778SEMIHARMONIC5
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_contact24676SEMIHARMONIC4
LS refinement shellResolution: 2.47→2.53 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.266 -1.18 %
Rwork0.238 6278 -
all0.238 6353 -
obs--87.32 %

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