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- PDB-4aj1: rat LDHA in complex with N-(2-(methylamino)-1,3-benzothiazol-6-yl... -

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Basic information

Entry
Database: PDB / ID: 4aj1
Titlerat LDHA in complex with N-(2-(methylamino)-1,3-benzothiazol-6-yl) acetamide
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 / Regulation of pyruvate metabolism / sperm fibrous sheath / pyruvate catabolic process / L-lactate dehydrogenase / cellular response to phorbol 13-acetate 12-myristate / oxidoreductase complex / pyruvate metabolic process / L-lactate dehydrogenase (NAD+) activity ...lactate dehydrogenase activity / Pyruvate metabolism / Regulation of pyruvate metabolism / sperm fibrous sheath / pyruvate catabolic process / L-lactate dehydrogenase / cellular response to phorbol 13-acetate 12-myristate / oxidoreductase complex / pyruvate metabolic process / L-lactate dehydrogenase (NAD+) activity / NAD+ metabolic process / lactate metabolic process / glucose catabolic process to lactate via pyruvate / response to cAMP / response to glucose / skeletal muscle tissue development / response to nutrient / response to hydrogen peroxide / liver development / response to estrogen / kinase binding / NAD binding / response to hypoxia / positive regulation of apoptotic process / response to xenobiotic stimulus / mitochondrion / identical protein binding / 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
N-(2-METHYLAMINO)-1,3-BENZOTHIAZOL-6-YL)ACETAMIDE / MALONATE ION / OXAMIC ACID / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsTucker, J.A. / Brassington, C. / Hassall, G. / Vogtherr, M. / Ward, R. / Tart, J. / Davies, G.
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 15, 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
Revision 1.3May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)147,61221
Polymers145,4534
Non-polymers2,15917
Water18,4651025
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area24620 Å2
ΔGint-103.5 kcal/mol
Surface area39880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.241, 81.914, 128.869
Angle α, β, γ (deg.)90.00, 96.18, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.77667, 0.09653, 0.62246), (0.0957, -0.95863, 0.26807), (0.62259, 0.26777, 0.73531)6.00403, -9.84277, -0.72301
2given(0.74792, 0.11233, -0.65422), (0.11397, -0.99267, -0.04015), (-0.65393, -0.04454, -0.75524)23.83758, -0.65606, 64.20519
3given(-0.97809, -0.20556, 0.03297), (-0.20753, 0.95016, -0.23265), (0.0165, -0.23439, -0.972)27.23637, 10.23386, 61.17541

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Components

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Protein , 1 types, 4 molecules ABCD

#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: MUSCLE / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): STAR / References: UniProt: P04642, L-lactate dehydrogenase

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Non-polymers , 5 types, 1042 molecules

#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical
ChemComp-AJ1 / N-(2-METHYLAMINO)-1,3-BENZOTHIAZOL-6-YL)ACETAMIDE


Mass: 221.279 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H11N3OS
#4: Chemical
ChemComp-MLI / MALONATE ION


Mass: 102.046 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H2O4
#5: Chemical ChemComp-OXM / OXAMIC ACID


Mass: 89.050 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3NO3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1025 / 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: 1.5 M NA 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: Dec 8, 2008 / Details: VARIMAXHF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.87→64.06 Å / Num. obs: 78548 / % possible obs: 73.8 % / Observed criterion σ(I): 2 / Redundancy: 2.81 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 8.3
Reflection shellResolution: 1.87→1.94 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.27 / Mean I/σ(I) obs: 2.2 / % possible all: 33.7

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Processing

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

Resolution: 1.87→49.37 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.936 / SU B: 6.652 / SU ML: 0.105 / Cross valid method: THROUGHOUT / ESU R: 0.232 / ESU R Free: 0.191 / 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
Rfree0.23109 3860 4.9 %RANDOM
Rwork0.17349 ---
obs0.17629 74127 73.31 %-
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: 22.782 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å2-0.03 Å2
2--0.01 Å20 Å2
3----0.02 Å2
Refinement stepCycle: LAST / Resolution: 1.87→49.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10025 0 146 1025 11196
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01910596
X-RAY DIFFRACTIONr_bond_other_d0.0020.026970
X-RAY DIFFRACTIONr_angle_refined_deg1.4821.97714399
X-RAY DIFFRACTIONr_angle_other_deg0.951317216
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.32251366
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.24325.264397
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.611151870
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6161541
X-RAY DIFFRACTIONr_chiral_restr0.0850.21685
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211853
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021962
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: 1.87→1.919 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.382 129 -
Rwork0.305 2328 -
obs--31.72 %
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)
10.1550.00860.07870.15290.04280.27220.0370.0183-0.01980.00030.0002-0.01520.0480.0312-0.03720.01690.00440.00090.0067-0.01190.031819.9381-14.686915.0904
20.1538-0.01350.10230.1791-0.07440.1982-0.0041-0.0020.0136-0.002-0.00260.0101-0.0132-0.01950.00670.00490.00130.00820.0042-0.00090.0312-1.690710.047918.9241
30.19360.05240.10880.242-0.01130.16650.004-0.03380.0223-0.0045-0.0041-0.0074-0.02070.03630.00010.0091-0.01490.01150.0383-0.01360.02227.49215.324240.3189
40.09840.07560.04210.2837-0.0210.22250.0414-0.0729-0.02590.0353-0.01810.00940.0315-0.0303-0.02330.0226-0.0272-0.0040.06110.0260.020510.9002-11.130250.2744
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 331
2X-RAY DIFFRACTION2B2 - 331
3X-RAY DIFFRACTION3C2 - 331
4X-RAY DIFFRACTION4D2 - 331

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