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- PDB-4aj2: rat LDHA in complex with 5-(2-chlorophenyl)-1H-tetrazole -

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Basic information

Entry
Database: PDB / ID: 4aj2
Titlerat LDHA in complex with 5-(2-chlorophenyl)-1H-tetrazole
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 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
5-(2-CHLOROPHENYL)-1H-TETRAZOLE / MALONATE ION / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsTucker, J.A. / Brassington, C. / Hassall, G. / Vogtherr, M. / Ward, R. / Tart, J. / Davies, G. / Frazer, M.
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)147,26819
Polymers145,4534
Non-polymers1,81515
Water19,6901093
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area24120 Å2
ΔGint-106.7 kcal/mol
Surface area41070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.000, 81.730, 128.780
Angle α, β, γ (deg.)90.00, 96.02, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.7739, 0.09863, 0.62558), (0.09319, -0.95931, 0.26653), (0.62641, 0.26456, 0.73322)6.04114, -9.80695, -0.87783
2given(0.74888, 0.10455, -0.65441), (0.1048, -0.99373, -0.03884), (-0.65437, -0.0395, -0.75514)23.77701, -0.57774, 64.27915
3given(-0.97927, -0.19975, 0.0337), (-0.20206, 0.95129, -0.23286), (0.01445, -0.23484, -0.97193)27.32334, 10.20269, 61.188

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Components

#1: Protein
L-LACTATE DEHYDROGENASE A CHAIN / 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical
ChemComp-52C / 5-(2-CHLOROPHENYL)-1H-TETRAZOLE


Mass: 180.594 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C7H5ClN4
#4: Chemical
ChemComp-MLI / MALONATE ION


Mass: 102.046 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H2O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1093 / 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 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: 1.75→68.9 Å / Num. obs: 91637 / % possible obs: 71.5 % / Observed criterion σ(I): 2 / Redundancy: 3.27 % / Biso Wilson estimate: 16.596 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 11.7
Reflection shellResolution: 1.75→1.82 Å / Redundancy: 1.39 % / Rmerge(I) obs: 0.21 / Mean I/σ(I) obs: 2.1 / % possible all: 9

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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: 1.75→49.21 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.948 / SU B: 4.491 / SU ML: 0.076 / Cross valid method: THROUGHOUT / ESU R: 0.166 / ESU R Free: 0.14 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. DISORDERED SIDE-CHAINS HAVE BEEN TRUNCATED. DIFFERENCE DENSITY CONSISTENT WITH AN ADDITIONAL BINDING SITE FOR TETRAZOLE LIGAND VISIBLE AT ...Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. DISORDERED SIDE-CHAINS HAVE BEEN TRUNCATED. DIFFERENCE DENSITY CONSISTENT WITH AN ADDITIONAL BINDING SITE FOR TETRAZOLE LIGAND VISIBLE AT SYMMETRY CONTACT, HOWEVER, NOT CLEAR ENOUGH TO BE MODELLED.
RfactorNum. reflection% reflectionSelection details
Rfree0.1935 4534 5 %RANDOM
Rwork0.15792 ---
obs0.15969 86532 71.06 %-
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: 22.584 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å2-0.02 Å2
2--0.01 Å20 Å2
3----0.03 Å2
Refinement stepCycle: LAST / Resolution: 1.75→49.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10093 0 122 1093 11308
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01910459
X-RAY DIFFRACTIONr_bond_other_d0.0010.027000
X-RAY DIFFRACTIONr_angle_refined_deg1.1021.97614166
X-RAY DIFFRACTIONr_angle_other_deg0.864317294
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.96651330
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.67525.232388
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.988151914
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9491540
X-RAY DIFFRACTIONr_chiral_restr0.0640.21670
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02111487
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021913
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: 1.753→1.799 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 33 -
Rwork0.26 575 -
obs--6.47 %
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)
10.06210.0730.03590.20310.05420.14910.01770.0127-0.0093-0.0080.0109-0.01480.02080.0277-0.02860.01530.00480.00060.0084-0.01070.017819.9922-14.955714.9759
20.0832-0.00990.07630.0999-0.03520.0869-0.0119-0.00270.00420.00030.00760.0105-0.0107-0.01540.00420.01630.00230.00330.0127-0.00230.0113-1.56510.212818.7822
30.15540.01550.08770.14180.02180.1132-0.0058-0.03180.016-0.012-0.00560.0047-0.0250.02790.01140.009-0.0150.00140.0423-0.00550.009527.557715.574640.4021
40.12560.05750.04280.124-0.05280.11290.0404-0.0696-0.0240.0037-0.0276-0.00980.0107-0.0258-0.01290.0198-0.0216-0.00590.04170.01460.005610.9677-11.2550.3811
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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