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- PDB-4aj4: rat LDHA in complex with 4-((2-allylsulfanyl-1,3-benzothizol-6-yl... -

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Basic information

Entry
Database: PDB / ID: 4aj4
Titlerat LDHA in complex with 4-((2-allylsulfanyl-1,3-benzothizol-6-yl) amino)-4-oxo-butanoic 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 / : / L-lactate dehydrogenase / NAD metabolic process / lactate metabolic process / L-lactate dehydrogenase activity ...lactate dehydrogenase activity / Pyruvate metabolism / sperm fibrous sheath / pyruvate catabolic process / oxidoreductase complex / : / L-lactate dehydrogenase / NAD metabolic process / lactate metabolic process / L-lactate dehydrogenase activity / glucose catabolic process to lactate via pyruvate / pyruvate metabolic process / 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 / 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
MALONATE ION / Chem-VAB / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 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)148,08416
Polymers145,9784
Non-polymers2,10612
Water16,123895
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area22780 Å2
ΔGint-113.2 kcal/mol
Surface area40790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.205, 82.066, 128.799
Angle α, β, γ (deg.)90.00, 96.17, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.77399, 0.09751, 0.62565), (0.09546, -0.95881, 0.26752), (0.62596, 0.26678, 0.7328)5.92938, -9.85462, -0.73539
2given(0.74757, 0.10309, -0.65613), (0.10208, -0.99398, -0.03986), (-0.65629, -0.03718, -0.75359)23.88788, -0.56273, 64.22585
3given(-0.98024, -0.19443, 0.03637), (-0.19747, 0.95132, -0.23664), (0.01141, -0.23915, -0.97092)27.2496, 10.24928, 61.19145

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Components

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


Mass: 36494.434 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
#2: Chemical
ChemComp-MLI / MALONATE ION


Mass: 102.046 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H2O4
#3: Chemical
ChemComp-VAB / 4-oxo-4-{[2-(prop-2-en-1-ylsulfanyl)-1,3-benzothiazol-6-yl]amino}butanoic acid


Mass: 322.403 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H14N2O3S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 895 / 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 % GYCEROL

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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: Jul 21, 2009 / Details: VARIMAXHF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.9→27.63 Å / Num. obs: 71058 / % possible obs: 70 % / Observed criterion σ(I): 2 / Redundancy: 2.95 % / Rmerge(I) obs: 0.35 / Net I/σ(I): 9.8
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 2.27 % / Rmerge(I) obs: 0.35 / Mean I/σ(I) obs: 2 / % possible all: 30.6

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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: 1.9→27.49 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.943 / SU B: 7.744 / SU ML: 0.119 / Cross valid method: THROUGHOUT / ESU R: 0.304 / ESU R Free: 0.219 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING RIDING POSITIONS. U VALUES WITH TLS ADDED. DISORDERED SIDE-CHAINS HAVE BEEN TRUNCATED.
RfactorNum. reflection% reflectionSelection details
Rfree0.24551 3492 5 %RANDOM
Rwork0.19522 ---
obs0.19773 66942 69.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.849 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å2-0.15 Å2
2--0.08 Å20 Å2
3----0.12 Å2
Refinement stepCycle: LAST / Resolution: 1.9→27.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10043 0 140 895 11078
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01910505
X-RAY DIFFRACTIONr_bond_other_d0.0010.026931
X-RAY DIFFRACTIONr_angle_refined_deg1.4411.97214267
X-RAY DIFFRACTIONr_angle_other_deg0.938317117
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.41451350
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.12225.306392
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.383151851
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.0691540
X-RAY DIFFRACTIONr_chiral_restr0.0810.21672
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211728
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021944
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: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.369 95 -
Rwork0.298 2086 -
obs--29.19 %
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)
10.33330.12780.10140.45840.06650.56250.04750.0249-0.0657-0.0152-0.0022-0.05620.06320.0611-0.04520.01630.0071-0.00370.0114-0.01370.03120.0356-14.420814.8802
20.3256-0.04040.15210.334-0.10190.4177-0.0211-0.00830.0396-0.00230.01250.0252-0.0396-0.04510.00850.0115-0.00130.00830.0119-0.00670.0253-1.580810.119118.8862
30.48740.03270.16330.43350.00650.4696-0.0014-0.10650.06170.0145-0.0024-0.0256-0.06890.0860.00380.0183-0.02520.00940.0637-0.02530.019627.448215.403640.2697
40.3360.18240.06660.4526-0.03490.56620.0625-0.1649-0.04980.0692-0.02170.01130.0496-0.0364-0.04090.0243-0.0286-0.00610.10250.03310.015910.8768-11.009550.3097
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 332
2X-RAY DIFFRACTION2B2 - 332
3X-RAY DIFFRACTION3C2 - 332
4X-RAY DIFFRACTION4D2 - 332

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