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- PDB-4aje: rat LDHA in complex with 2-(4-bromophenoxy)propanedioic acid -

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Basic information

Entry
Database: PDB / ID: 4aje
Titlerat LDHA in complex with 2-(4-bromophenoxy)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 / 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
2-(4-BROMANYLPHENOXY)PROPANEDIOIC ACID / MALONATE ION / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsTucker, J.A. / Brassington, C. / Hassall, G. / Vogtherr, M. / Ward, R. / Tart, J. / Davies, G. / 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 / Source and taxonomy / Category: diffrn_source / entity_src_gen
Item: _diffrn_source.type / _entity_src_gen.gene_src_common_name ..._diffrn_source.type / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_gene_src_scientific_name / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_strain
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)147,34016
Polymers145,4534
Non-polymers1,88712
Water12,701705
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area22690 Å2
ΔGint-120.6 kcal/mol
Surface area39970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.298, 82.510, 129.113
Angle α, β, γ (deg.)90.00, 96.19, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.77579, 0.0962, 0.62361), (0.09573, -0.95893, 0.26701), (0.62369, 0.26684, 0.73472)6.0054, -9.9801, -0.73906
2given(0.74946, 0.10226, -0.6541), (0.10195, -0.99404, -0.03859), (-0.65415, -0.03777, -0.75542)23.87828, -0.67785, 64.27093
3given(-0.98105, -0.19146, 0.02984), (-0.19297, 0.95127, -0.24052), (0.01766, -0.24172, -0.97019)27.43847, 10.27174, 61.12556

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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 BL21(DE3) (bacteria) / Variant (production host): STAR / References: UniProt: P04642, L-lactate dehydrogenase
#2: Chemical
ChemComp-2B4 / 2-(4-BROMANYLPHENOXY)PROPANEDIOIC ACID


Mass: 275.053 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H7BrO5
#3: Chemical
ChemComp-MLI / MALONATE ION


Mass: 102.046 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H2O4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 705 / 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: Oct 6, 2009 / Details: VARIMAXHF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.35→30.87 Å / Num. obs: 54228 / % possible obs: 99.8 % / Observed criterion σ(I): 2 / Redundancy: 3.44 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 8.3
Reflection shellResolution: 2.35→2.43 Å / Redundancy: 3.48 % / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 2.7 / % possible all: 99.6

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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: 2.35→28.99 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.911 / SU B: 14.86 / SU ML: 0.192 / Cross valid method: THROUGHOUT / ESU R: 0.581 / ESU R Free: 0.301 / 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
Rfree0.2718 2732 5.1 %RANDOM
Rwork0.20197 ---
obs0.20544 51074 98.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.278 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å2-0.14 Å2
2--0.14 Å20 Å2
3----0.18 Å2
Refinement stepCycle: LAST / Resolution: 2.35→28.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9970 0 113 705 10788
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01910340
X-RAY DIFFRACTIONr_bond_other_d0.0010.026766
X-RAY DIFFRACTIONr_angle_refined_deg1.4831.97114051
X-RAY DIFFRACTIONr_angle_other_deg0.951316704
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.59651333
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.54925.196383
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.275151787
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.3951540
X-RAY DIFFRACTIONr_chiral_restr0.0830.21667
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02111503
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021921
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: 2.35→2.411 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.372 181 -
Rwork0.266 3686 -
obs--99.36 %
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)
10.34950.0330.10780.21660.10790.52990.06810.0629-0.1124-0.02850.0098-0.03960.13210.0688-0.0780.06570.0145-0.01780.031-0.02790.050619.9609-14.583815.1411
20.3572-0.02680.16610.27250.01010.50050.0030.00520.0413-0.02740.0060.038-0.0509-0.0828-0.0090.0272-0.00710.01240.03660.00140.027-1.63829.985318.9245
30.5141-0.01910.13090.27990.00590.5198-0.0005-0.11110.0919-0.01210.0068-0.0223-0.08460.1222-0.00630.0268-0.04030.01260.0872-0.03690.023327.64715.311740.2322
40.4050.06010.08540.1334-0.03880.5040.0744-0.2075-0.090.0245-0.0050.02340.1111-0.0447-0.06950.0515-0.0434-0.01430.1190.0490.035910.9144-11.074550.2838
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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