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- PDB-4ajk: rat LDHA in complex with N-(2-(methylamino)-1,3-benzothiazol-6-yl... -

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Basic information

Entry
Database: PDB / ID: 4ajk
Titlerat LDHA in complex with N-(2-(methylamino)-1,3-benzothiazol-6-yl) acetamide
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
Chem-88S / MALONATE ION / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.03 Å
AuthorsTucker, J.A. / Brassington, C. / Hassall, G. / Vogtherr, M. / Ward, R. / Tart, J. / Davies, G. / 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)147,65919
Polymers145,4534
Non-polymers2,20615
Water20,7531152
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area24350 Å2
ΔGint-104.6 kcal/mol
Surface area39320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.174, 81.749, 128.975
Angle α, β, γ (deg.)90.00, 96.14, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.77527, 0.09934, 0.62376), (0.09446, -0.95821, 0.27001), (0.62452, 0.26825, 0.73349)5.99498, -9.88906, -0.72625
2given(0.74714, 0.1071, -0.65599), (0.10816, -0.99337, -0.03899), (-0.65581, -0.04182, -0.75376)23.90583, -0.61293, 64.3019
3given(-0.97913, -0.20015, 0.03523), (-0.20276, 0.95038, -0.23592), (0.01374, -0.23814, -0.97113)27.26304, 10.25473, 61.28599

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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-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.: 8 / 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.: 1152 / 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: 1.4 M 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: Apr 21, 2010 / Details: VARIMAXHF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.03→128.23 Å / Num. obs: 81625 / % possible obs: 98.8 % / Observed criterion σ(I): 2 / Redundancy: 3.5 % / Biso Wilson estimate: 21.35 Å2 / Rmerge(I) obs: 0.11 / Net I/σ(I): 9.1
Reflection shellResolution: 2.03→2.14 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 2.3 / % possible all: 95.4

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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: 2.03→29.39 Å / Cor.coef. Fo:Fc: 0.9543 / Cor.coef. Fo:Fc free: 0.929 / SU R Cruickshank DPI: 0.169 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.18 / SU Rfree Blow DPI: 0.147 / SU Rfree Cruickshank DPI: 0.145
Details: DISORDERED SIDE-CHAINS HAVE BEEN TRUNCATED. IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.1903 4080 5 %RANDOM
Rwork0.1474 ---
obs0.1496 81507 98.07 %-
Displacement parametersBiso mean: 24.05 Å2
Baniso -1Baniso -2Baniso -3
1-0.0452 Å20 Å22.0795 Å2
2---4.1608 Å20 Å2
3---4.1156 Å2
Refine analyzeLuzzati coordinate error obs: 0.208 Å
Refinement stepCycle: LAST / Resolution: 2.03→29.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9971 0 150 1152 11273
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110407HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1214136HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3607SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes239HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1527HARMONIC5
X-RAY DIFFRACTIONt_it10407HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.36
X-RAY DIFFRACTIONt_other_torsion16.02
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1369SEMIHARMONIC5
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_contact13707SEMIHARMONIC4
LS refinement shellResolution: 2.03→2.08 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2475 243 4.66 %
Rwork0.2019 4973 -
all0.204 5216 -
obs--98.07 %
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)
10.35830.04240.16860.21540.04750.72780.04630.0288-0.0863-0.01160.0163-0.0620.15110.088-0.06260.01820.009-0.0263-0.0673-0.0151-0.006219.9347-14.722615.103
20.35910.05950.13890.2580.02290.4588-0.0332-0.03460.050.00570.00750.0439-0.0723-0.07640.02570.02020.0076-0.0127-0.0375-0.0061-0.0073-1.605110.014219.0835
30.62740.11060.20090.2898-0.08710.6042-0.0203-0.1020.09040.00810.0004-0.0432-0.09940.08510.0199-0.0162-0.02-0.0047-0.0204-0.0299-0.042327.386315.453940.3351
40.36410.09290.11030.3547-0.00230.54920.0647-0.1901-0.06330.0842-0.01410.00210.1127-0.0713-0.0506-0.0002-0.0356-0.02890.03460.0448-0.047210.894-11.055350.2378
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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