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- PDB-4ajn: rat LDHA in complex with 2-((4-(2-((3-((2-methyl-1,3-benzothiazol... -

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Basic information

Entry
Database: PDB / ID: 4ajn
Titlerat LDHA in complex with 2-((4-(2-((3-((2-methyl-1,3-benzothiazol-6- yl)amino)-3-oxo-propyl)carbamoylamino)ethyl)phenyl)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 / 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 / NAD+ metabolic process ...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 / NAD+ metabolic process / L-lactate dehydrogenase (NAD+) activity / lactate metabolic process / homolactic fermentation / 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
Chem-88V / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsTucker, J.A. / Brassington, C. / Hassall, G. / Watson, M. / Ward, R. / Tart, J. / Davies, G. / Caputo, A. / Pearson, S.
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
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)147,5399
Polymers145,4534
Non-polymers2,0865
Water14,844824
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area21070 Å2
ΔGint-143.1 kcal/mol
Surface area40480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.222, 82.728, 129.481
Angle α, β, γ (deg.)90.00, 96.23, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.78118, 0.10057, 0.61615), (0.09621, -0.95576, 0.27798), (0.61685, 0.27644, 0.73694)0.09304, -0.12256, -0.00337
2given(0.75407, 0.09236, -0.65027), (0.09502, -0.99499, -0.03113), (-0.64988, -0.03832, -0.75907)23.73263, -0.6058, 64.3206
3given(-0.98184, -0.18823, 0.02354), (-0.18803, 0.94925, -0.25211), (0.02511, -0.25196, -0.96741)27.1378, 10.4855, 61.16097

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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: 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-88V / (4-{2-[({3-[(2-METHYL-1,3-BENZOTHIAZOL-6-YL)AMINO]-3-OXOPROPYL}CARBAMOYL)AMINO]ETHYL}BENZYL)PROPANEDIOIC ACID


Mass: 498.551 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H26N4O6S
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 824 / 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: 1.5M 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: Jun 29, 2010 / Details: VARIMAXHF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.1→128.72 Å / Num. obs: 75861 / % possible obs: 99.5 % / Observed criterion σ(I): 2 / Redundancy: 3.6 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 9
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 2.2 / % possible all: 99.8

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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: 2.1→65.59 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.925 / SU B: 9.759 / SU ML: 0.139 / Cross valid method: THROUGHOUT / ESU R: 0.242 / ESU R Free: 0.188 / 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
Rfree0.22371 3795 5 %RANDOM
Rwork0.17883 ---
obs0.18111 71902 99.29 %-
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: 23.472 Å2
Baniso -1Baniso -2Baniso -3
1--0.13 Å20 Å2-0.03 Å2
2--0.03 Å20 Å2
3---0.09 Å2
Refinement stepCycle: LAST / Resolution: 2.1→65.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9947 0 146 824 10917
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01910406
X-RAY DIFFRACTIONr_bond_other_d0.0010.026799
X-RAY DIFFRACTIONr_angle_refined_deg1.4091.95814160
X-RAY DIFFRACTIONr_angle_other_deg0.961316768
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.69751338
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.18625.052384
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.789151768
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9851541
X-RAY DIFFRACTIONr_chiral_restr0.0840.21666
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211671
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021970
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: 2.101→2.156 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.289 246 -
Rwork0.241 5207 -
obs--99.47 %
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)
10.31060.07220.19260.23140.08850.4970.10260.0829-0.04730.0210.00550.00730.11260.1171-0.1080.05030.034-0.01680.0367-0.03030.0519.7752-14.751815.3616
20.2883-0.06050.24140.2489-0.05010.3597-0.008-0.02660.01120.00030.01360.0437-0.0476-0.042-0.00560.036-0.00620.02180.01610.00630.0557-1.751210.201119.0797
30.38760.00630.15550.3288-0.11160.42220.0018-0.09790.0465-0.018-0.0186-0.0048-0.09750.11340.01670.0413-0.05220.01360.0968-0.02290.027127.258515.413540.3575
40.26190.05220.13460.23530.01230.41460.0628-0.166-0.0357-0.01250.00620.00560.0876-0.0646-0.0690.0413-0.0398-0.00920.11960.02780.022110.7513-10.846350.4165
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 331
2X-RAY DIFFRACTION2B2 - 331
3X-RAY DIFFRACTION3C2 - 331
4X-RAY DIFFRACTION4D2 - 331

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