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- PDB-9bk3: Crystal structure of Lactate dehydrogenase in complex with 4-((4-... -

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Basic information

Entry
Database: PDB / ID: 9bk3
TitleCrystal structure of Lactate dehydrogenase in complex with 4-((4-(1-methyl-1H-imidazole-2-carbonyl)phenyl)amino)-4-oxo-2-(4-(trifluoromethyl)phenyl)butanoic acid (R-enantiomer, orthorhombic P form)
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE/INHIBITOR / Lactate dehydrogenase / OXIDOREDUCTASE / LDHA / Inhibitor Complex / 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-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 domain superfamily
Similarity search - Domain/homology
: / MALONATE ION / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsLovell, S. / Cooper, A. / Battaile, K.P. / Sharma, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/Office of the DirectorS10OD030394 United States
CitationJournal: Eur.J.Med.Chem. / Year: 2024
Title: Synthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer.
Authors: Sharma, H. / Mondal, S. / Urquiza, U. / Esparza, C. / Bartlett, S. / Santa-Pinter, L. / Hill, H. / White, M. / Sharma, P. / Luckett-Chastain, L. / Cooper, A. / Rasel, M. / Gao, P. / ...Authors: Sharma, H. / Mondal, S. / Urquiza, U. / Esparza, C. / Bartlett, S. / Santa-Pinter, L. / Hill, H. / White, M. / Sharma, P. / Luckett-Chastain, L. / Cooper, A. / Rasel, M. / Gao, P. / Battaile, K.P. / Shukla, S.K. / Lovell, S. / Ihnat, M.A.
History
DepositionApr 26, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)157,37012
Polymers156,4774
Non-polymers8938
Water81145
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area22290 Å2
ΔGint-174 kcal/mol
Surface area41300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.077, 103.698, 189.506
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: 39119.180 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LDHA, PIG19 / Plasmid: pTBSG / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): pRARE / References: UniProt: P00338, L-lactate dehydrogenase
#2: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-MLI / MALONATE ION


Mass: 102.046 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H2O4
#4: Chemical ChemComp-A1AR0 / (2R)-4-[4-(1-methyl-1H-imidazole-2-carbonyl)anilino]-4-oxo-2-[4-(trifluoromethyl)phenyl]butanoic acid


Mass: 445.391 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18F3N3O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.2 Å3/Da / Density % sol: 44.1 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: Index HT C9: 1.1 M sodium malonate, 0.1 M HEPES pH 7.5, 0.5 %v/v Jeffamine ED-2001, LDHA at 11.9 mg/mL. 2mM inhibitor added prior to crystallization. plate Anne-clover-6, A2. Puck: PSL-1912, ...Details: Index HT C9: 1.1 M sodium malonate, 0.1 M HEPES pH 7.5, 0.5 %v/v Jeffamine ED-2001, LDHA at 11.9 mg/mL. 2mM inhibitor added prior to crystallization. plate Anne-clover-6, A2. Puck: PSL-1912, Cryo: 3.4 M sodium malonate pH 7.5.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 19-ID / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 XE 9M / Detector: PIXEL / Date: Mar 5, 2023
RadiationMonochromator: Double Crystal Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.4→49.51 Å / Num. obs: 54912 / % possible obs: 100 % / Redundancy: 13.5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.099 / Rpim(I) all: 0.028 / Rrim(I) all: 0.103 / Χ2: 1.02 / Net I/σ(I): 16.4 / Num. measured all: 739694
Reflection shellResolution: 2.4→2.47 Å / % possible obs: 100 % / Redundancy: 12.4 % / Rmerge(I) obs: 1.702 / Num. measured all: 55106 / Num. unique obs: 4452 / CC1/2: 0.663 / Rpim(I) all: 0.501 / Rrim(I) all: 1.776 / Χ2: 1 / Net I/σ(I) obs: 1.5

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→47.38 Å / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.11 / Phase error: 35.62 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2901 2870 5.24 %
Rwork0.2285 --
obs0.2318 54800 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.4→47.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9738 0 57 45 9840
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0019958
X-RAY DIFFRACTIONf_angle_d0.41113537
X-RAY DIFFRACTIONf_dihedral_angle_d11.223574
X-RAY DIFFRACTIONf_chiral_restr0.0411622
X-RAY DIFFRACTIONf_plane_restr0.0021704
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.440.42021110.36522457X-RAY DIFFRACTION100
2.44-2.480.41031240.35282433X-RAY DIFFRACTION100
2.48-2.530.47271520.35892446X-RAY DIFFRACTION100
2.53-2.580.45341440.33972424X-RAY DIFFRACTION100
2.58-2.630.40051520.322407X-RAY DIFFRACTION100
2.63-2.680.34381230.30082463X-RAY DIFFRACTION100
2.68-2.750.32821420.30542432X-RAY DIFFRACTION100
2.75-2.820.37011290.30082462X-RAY DIFFRACTION100
2.82-2.890.39011140.30862482X-RAY DIFFRACTION100
2.89-2.980.35041390.30112441X-RAY DIFFRACTION100
2.98-3.070.3611380.29092466X-RAY DIFFRACTION100
3.07-3.180.34351390.2882456X-RAY DIFFRACTION100
3.18-3.310.3661260.26982473X-RAY DIFFRACTION100
3.31-3.460.33361430.2622445X-RAY DIFFRACTION100
3.46-3.640.30741300.25252479X-RAY DIFFRACTION100
3.64-3.870.30061390.22152488X-RAY DIFFRACTION100
3.87-4.170.27051550.20772470X-RAY DIFFRACTION100
4.17-4.590.25651360.17652505X-RAY DIFFRACTION100
4.59-5.250.23931350.17162515X-RAY DIFFRACTION100
5.25-6.620.24721470.20312544X-RAY DIFFRACTION100
6.62-47.380.20891520.17162642X-RAY DIFFRACTION99

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