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- PDB-4ajj: rat LDHA in complex with 2-((3,4-dimethoxyphenyl)methyl))propaned... -

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Basic information

Entry
Database: PDB / ID: 4ajj
Titlerat LDHA in complex with 2-((3,4-dimethoxyphenyl)methyl))propanedioic acid and N-(2-methyl-1,3-benzothiazol-6-yl)-3-ureido-propanamide
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 / L-lactate dehydrogenase (NAD+) activity / pyruvate 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 / L-lactate dehydrogenase (NAD+) activity / pyruvate metabolic process / 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-((3,4-DIMETHOXYPHENYL)METHYL))PROPANEDIOIC ACID / Chem-88S / 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. / Patel, J. / Greenwood, R.
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)147,44914
Polymers145,4534
Non-polymers1,99610
Water20,6451146
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area23010 Å2
ΔGint-123.9 kcal/mol
Surface area41170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.141, 81.892, 128.986
Angle α, β, γ (deg.)90.00, 96.06, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.77748, 0.10069, 0.62079), (0.09449, -0.95719, 0.2736), (0.62177, 0.27137, 0.73469)6.14813, -9.89883, -0.7355
2given(0.74928, 0.10287, -0.65422), (0.10345, -0.99392, -0.03781), (-0.65413, -0.03935, -0.75536)23.80082, -0.48606, 64.34377
3given(-0.97974, -0.19765, 0.03229), (-0.19952, 0.94931, -0.24292), (0.01736, -0.24444, -0.96951)27.31471, 10.41541, 61.1702

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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 , 6 types, 1156 molecules

#2: Chemical
ChemComp-88S / N-(2-METHYL-1,3-BENZOTHIAZOL-6-YL)-3-UREIDO-PROPANAMIDE


Mass: 278.330 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H14N4O2S
#3: Chemical ChemComp-MLI / MALONATE ION


Mass: 102.046 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H2O4
#4: Chemical ChemComp-88R / 2-((3,4-DIMETHOXYPHENYL)METHYL))PROPANEDIOIC ACID


Mass: 254.236 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H14O6
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 1146 / 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: May 17, 2010 / 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→128.27 Å / Num. obs: 99037 / % possible obs: 76.5 % / Observed criterion σ(I): 2 / Redundancy: 3.2 % / Biso Wilson estimate: 19.98 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 14.3
Reflection shellResolution: 1.75→1.84 Å / Redundancy: 1.6 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 1.7 / % possible all: 14.9

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INTERNAL RAT LDHA STRUCTURE

Resolution: 1.75→25.62 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.9482 / SU R Cruickshank DPI: 0.128 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.134 / SU Rfree Blow DPI: 0.114 / SU Rfree Cruickshank DPI: 0.113
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY. DISORDERED SIDE-CHAINS HAVE BEEN TRUNCATED
RfactorNum. reflection% reflectionSelection details
Rfree0.173 4927 4.98 %RANDOM
Rwork0.1444 ---
obs0.1458 98947 76.37 %-
Displacement parametersBiso mean: 22.48 Å2
Baniso -1Baniso -2Baniso -3
1--0.2256 Å20 Å23.2205 Å2
2---0.5044 Å20 Å2
3---0.73 Å2
Refine analyzeLuzzati coordinate error obs: 0.183 Å
Refinement stepCycle: LAST / Resolution: 1.75→25.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10079 0 136 1146 11361
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110523HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0414292HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3707SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes249HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1535HARMONIC5
X-RAY DIFFRACTIONt_it10523HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.31
X-RAY DIFFRACTIONt_other_torsion15.99
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1378SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact13740SEMIHARMONIC4
LS refinement shellResolution: 1.75→1.79 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2706 48 6.56 %
Rwork0.2601 684 -
all0.2608 732 -
obs--76.37 %
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)
10.38020.04360.14070.26950.03390.57130.04440.0256-0.0719-0.01120.0089-0.05490.11220.0712-0.05330.00050.0063-0.0136-0.0381-0.0134-0.009220.0405-14.735815.1052
20.36370.05030.12760.2915-0.03390.3639-0.0251-0.02730.0445-0.00270.00890.0294-0.0475-0.06490.0162-0.00240.0087-0.0015-0.0133-0.0051-0.0167-1.517110.335118.7518
30.53850.04730.15420.3934-0.08430.4492-0.0103-0.10460.09010.016-0.0113-0.0373-0.07110.07540.0216-0.0192-0.01860.00090.004-0.0299-0.040427.566715.366240.293
40.48850.06460.10540.3985-0.03090.4870.0659-0.2052-0.0660.0933-0.02030.01670.0966-0.0954-0.0456-0.0165-0.0413-0.01010.05290.0386-0.072811.0055-11.135650.4459
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A
2X-RAY DIFFRACTION2CHAIN B
3X-RAY DIFFRACTION3CHAIN C
4X-RAY DIFFRACTION4CHAIN D

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