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- PDB-5ixy: Lactate Dehydrogenase in complex with hydroxylactam inhibitor com... -

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Basic information

Entry
Database: PDB / ID: 5ixy
TitleLactate Dehydrogenase in complex with hydroxylactam inhibitor compound 31: (2~{S})-5-(2-chlorophenyl)sulfanyl-2-(4-morpholin-4-ylphenyl)-4-oxidanyl-2-thiophen-3-yl-1,3-dihydropyridin-6-one
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIREDUCTASE/OXIREDUCTASE INHIBITOR / oxidoreductase tetramer / OXIREDUCTASE-OXIREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


L-lactate dehydrogenase / oxidoreductase complex / L-lactate dehydrogenase activity / Pyruvate metabolism / lactate metabolic process / pyruvate metabolic process / substantia nigra development / Regulation of pyruvate metabolism / glycolytic process / cadherin binding ...L-lactate dehydrogenase / oxidoreductase complex / L-lactate dehydrogenase activity / Pyruvate metabolism / lactate metabolic process / pyruvate metabolic process / 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-GN2 / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsChen, Z. / Eigenbrot, C.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice.
Authors: Purkey, H.E. / 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. / Gao, Z. / Ge, H. / Hitz, ...Authors: Purkey, H.E. / 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. / Gao, Z. / Ge, H. / Hitz, A. / Ho, Q. / Labadie, S.S. / 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. / Wei, B. / Yen, I. / Yue, Q. / Zhang, H. / Zhou, A.
History
DepositionMar 23, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 14, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 9, 2016Group: Database references
Revision 1.2Sep 27, 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 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)151,73619
Polymers146,4144
Non-polymers5,32215
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area28340 Å2
ΔGint-271 kcal/mol
Surface area43650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.452, 80.696, 102.236
Angle α, β, γ (deg.)90.00, 97.90, 90.00
Int Tables number4
Space group name H-MP1211

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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-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


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


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-GN2 / (2~{S})-5-(2-chlorophenyl)sulfanyl-2-(4-morpholin-4-ylphenyl)-4-oxidanyl-2-thiophen-3-yl-1,3-dihydropyridin-6-one


Mass: 499.045 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H23ClN2O3S2

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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: 2.19 Å3/Da / Density % sol: 43.82 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: PEG 3350, sodium malonate

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 7, 2013
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 3→33.1 Å / Num. obs: 22595 / % possible obs: 95.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.1 % / Biso Wilson estimate: 49 Å2 / Rsym value: 0.103 / Net I/σ(I): 10.4
Reflection shellResolution: 3→3.11 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.402 / Mean I/σ(I) obs: 3.4

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1I10

1i10


Resolution: 3→33.1 Å / Cor.coef. Fo:Fc: 0.8755 / Cor.coef. Fo:Fc free: 0.8155 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.573
RfactorNum. reflection% reflectionSelection details
Rfree0.2791 506 2.24 %RANDOM
Rwork0.2362 ---
obs0.2371 22595 88.49 %-
Displacement parametersBiso mean: 55.38 Å2
Baniso -1Baniso -2Baniso -3
1-2.1874 Å20 Å2-1.5836 Å2
2---1.2483 Å20 Å2
3----0.939 Å2
Refine analyzeLuzzati coordinate error obs: 0.464 Å
Refinement stepCycle: 1 / Resolution: 3→33.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10250 0 343 0 10593
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00810794HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0814653HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3783SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes256HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1572HARMONIC5
X-RAY DIFFRACTIONt_it10794HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.1
X-RAY DIFFRACTIONt_other_torsion19.73
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1398SEMIHARMONIC5
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_contact12268SEMIHARMONIC4
LS refinement shellResolution: 3→3.15 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.3451 62 2.44 %
Rwork0.2755 2479 -
all0.2771 2541 -
obs--88.49 %

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