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- PDB-4aji: rat LDHA in complex with 2-((3,4-dimethoxyphenyl)methyl))propaned... -

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Basic information

Entry
Database: PDB / ID: 4aji
Titlerat LDHA in complex with 2-((3,4-dimethoxyphenyl)methyl))propanedioic acid
ComponentsL-LACTATE DEHYDROGENASE A CHAIN
KeywordsOXIDOREDUCTASE/INHIBITOR / OXIDOREDUCTASE-INHIBITOR COMPLEX / FRAGMENT BASED LEAD GENERATED INHIBITORS
Function / homology
Function and homology information


lactate dehydrogenase activity / Pyruvate metabolism / sperm fibrous sheath / pyruvate catabolic process / oxidoreductase complex / cellular response to extracellular stimulus / lactate metabolic process / L-lactate dehydrogenase / L-lactate dehydrogenase activity / NAD metabolic process ...lactate dehydrogenase activity / Pyruvate metabolism / sperm fibrous sheath / pyruvate catabolic process / oxidoreductase complex / cellular response to extracellular stimulus / lactate metabolic process / L-lactate dehydrogenase / L-lactate dehydrogenase activity / NAD metabolic process / pyruvate metabolic process / glucose catabolic process to lactate via pyruvate / response to glucose / skeletal muscle tissue development / response to cAMP / response to nutrient / liver development / response to hydrogen peroxide / response to organic cyclic compound / kinase binding / response to estrogen / NAD binding / response to hypoxia / response to xenobiotic stimulus / positive regulation of apoptotic process / mitochondrion / identical protein binding / cytosol
Similarity search - Function
L-lactate dehydrogenase active site. / L-lactate dehydrogenase / 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 active site. / L-lactate dehydrogenase / 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
2-((3,4-DIMETHOXYPHENYL)METHYL))PROPANEDIOIC ACID / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.93 Å
AuthorsTucker, J.A. / Brassington, C. / Hassall, G. / Vogtherr, M. / Ward, R. / Tart, J. / Davies, G. / Debreczeni, J.
CitationJournal: J.Med.Chem. / Year: 2012
Title: The Design and Synthesis of Novel Lactate Dehydrogenase a Inhibitors by Fragment-Based Lead Generation
Authors: Ward, R. / Brassington, C. / Breeze, A.L. / Caputo, A. / Critchlow, S. / Davies, G. / Goodwin, L. / Hassall, G. / Greenwood, R. / Holdgate, G. / Mrosek, M. / Norman, R.A. / Pearson, S. / ...Authors: Ward, R. / Brassington, C. / Breeze, A.L. / Caputo, A. / Critchlow, S. / Davies, G. / Goodwin, L. / Hassall, G. / Greenwood, R. / Holdgate, G. / Mrosek, M. / Norman, R.A. / Pearson, S. / Tart, J. / Tucker, J.A. / Vogtherr, M. / Whittaker, D. / Wingfield, J. / Winter, J. / Hudson, K.
History
DepositionFeb 16, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 21, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2012Group: Other
Revision 1.2Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type

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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)146,4708
Polymers145,4534
Non-polymers1,0174
Water13,655758
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area20910 Å2
ΔGint-137.5 kcal/mol
Surface area41130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.923, 81.649, 128.994
Angle α, β, γ (deg.)90.00, 96.08, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.78272, 0.08951, 0.6159), (0.10433, -0.95673, 0.27164), (0.61356, 0.27688, 0.73951)6.1545, -10.00971, -0.61392
2given(0.75075, 0.12168, -0.64928), (0.12454, -0.99133, -0.04178), (-0.64874, -0.0495, -0.7594)23.7067, -0.67712, 64.26215
3given(-0.97669, -0.21284, 0.02801), (-0.21328, 0.94721, -0.2394), (0.02442, -0.23979, -0.97052)27.18979, 10.46343, 61.07696

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Components

#1: Protein
L-LACTATE DEHYDROGENASE A CHAIN / LACTATE DEHYDROGENASE A / LDH-A / LDH MUSCLE SUBUNIT / LDH-M


Mass: 36363.238 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) RATTUS NORVEGICUS (Norway rat) / Tissue: MUSCLESkeletal muscle / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): STAR / References: UniProt: P04642, L-lactate dehydrogenase
#2: Chemical
ChemComp-88R / 2-((3,4-DIMETHOXYPHENYL)METHYL))PROPANEDIOIC ACID


Mass: 254.236 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H14O6
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 758 / 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: 2.32 Å3/Da / Density % sol: 47 % / Description: NONE
Crystal growpH: 7 / Details: 1.4 M SODIUM MALONATE PH 7.0, 2% GLYCEROL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.54
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Feb 3, 2010 / Details: VARIMAXHF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.93→128.27 Å / Num. obs: 91505 / % possible obs: 94.8 % / Observed criterion σ(I): 2 / Redundancy: 3.4 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 12.6
Reflection shellResolution: 1.93→2.03 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 2 / % possible all: 71.3

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
XDSdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INTERNAL RAT LDHA STRUCTURE

Resolution: 1.93→68.88 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.944 / SU B: 6.748 / SU ML: 0.098 / Cross valid method: THROUGHOUT / ESU R: 0.164 / ESU R Free: 0.141 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED. DISORDERED SIDE-CHAINS HAVE BEEN TRUNCATED
RfactorNum. reflection% reflectionSelection details
Rfree0.19795 4555 5 %RANDOM
Rwork0.16205 ---
obs0.16386 86629 94.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 20.094 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å2-0.02 Å2
2--0.01 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.93→68.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10076 0 72 758 10906
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.01910394
X-RAY DIFFRACTIONr_bond_other_d0.0010.026877
X-RAY DIFFRACTIONr_angle_refined_deg1.2631.9714108
X-RAY DIFFRACTIONr_angle_other_deg0.885316994
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.20551332
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.06625.293393
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.565151870
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2331540
X-RAY DIFFRACTIONr_chiral_restr0.0730.21663
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.02111409
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021887
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.93→1.98 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.332 238 -
Rwork0.267 4244 -
obs--64.29 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.41680.03210.14790.23020.1070.56520.06080.0249-0.1095-0.02380.0054-0.04860.13610.0422-0.06620.06740.0049-0.00430.0059-0.00940.068620.1483-14.630315.1309
20.50360.01410.1750.2307-0.03470.387-0.0074-0.05330.0686-0.0285-0.0010.0374-0.0468-0.07930.00840.04370.00110.01420.0197-0.00990.0398-1.709910.095718.919
30.58840.04350.15490.2617-0.00080.4066-0.0051-0.16770.11220.0055-0.0116-0.0274-0.07440.04660.01670.0322-0.02450.01690.0796-0.04410.041427.454415.512340.3071
40.47910.07780.17980.2868-0.01090.44370.0836-0.3069-0.10160.059-0.0212-0.01140.1103-0.1208-0.06250.0581-0.0513-0.00880.19990.0640.034410.7812-11.007350.2514
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 331
2X-RAY DIFFRACTION2B2 - 331
3X-RAY DIFFRACTION3C1 - 331
4X-RAY DIFFRACTION4D2 - 331

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