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- PDB-4al4: rat LDHA in complex with 2-((4-(2-((3-((2-methyl-1,3-benzothiazol... -

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Basic information

Entry
Database: PDB / ID: 4al4
Titlerat LDHA in complex with 2-((4-(2-((3-((2-methyl-1,3-benzothiazol-6- yl)amino)3-oxo-propyl)carbamoylamino)ethoxy)phenyl)methylpropanedioic 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
Chem-W7E / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsTucker, J.A. / Brassington, C. / Hassall, G. / Ward, R. / Tart, J. / Davies, G. / Hohson, M. / 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
DepositionMar 1, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 21, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2012Group: Other
Revision 1.2May 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)149,14712
Polymers145,4534
Non-polymers3,6948
Water17,997999
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area25780 Å2
ΔGint-141 kcal/mol
Surface area41860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.356, 82.696, 129.672
Angle α, β, γ (deg.)90.00, 96.49, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.78224, 0.10199, 0.61458), (0.09573, -0.95511, 0.28035), (0.61558, 0.27814, 0.73736)5.57585, -10.15153, -0.28883
2given(0.75621, 0.08189, -0.64918), (0.08752, -0.99588, -0.02368), (-0.64845, -0.03891, -0.76026)23.63514, -0.63274, 64.32001
3given(-0.98301, -0.18221, 0.02213), (-0.18169, 0.94881, -0.25836), (0.02608, -0.25799, -0.96579)26.81707, 10.64603, 61.21664

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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.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical
ChemComp-W7E / 2-[[4-[2-[[3-[(2-methyl-1,3-benzothiazol-6-yl)amino]-3-oxidanylidene-propyl]carbamoylamino]ethoxy]phenyl]methyl]propanedioic acid / 2-[[4-[2-[[3-[(2-methyl-1,3-benzothiazol-6-yl)amino]-3-oxo-propyl]carbamoylamino]ethoxy]phenyl]methyl]propanedioic acid


Mass: 514.551 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C24H26N4O7S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 999 / 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: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9748
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 2, 2010 / Details: MIRRORS
RadiationMonochromator: SI(311) OR SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9748 Å / Relative weight: 1
ReflectionResolution: 1.78→128.84 Å / Num. obs: 114880 / % possible obs: 91.7 % / Observed criterion σ(I): 2 / Redundancy: 3.2 % / Biso Wilson estimate: 21.15 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 12.2
Reflection shellResolution: 1.83→1.88 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 1.3 / % possible all: 66

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.11.2refinement
XDSVERSION MAY 10 2010data reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INTERNAL RAT LDHA STRUCTURE

Resolution: 1.78→64.42 Å / Cor.coef. Fo:Fc: 0.9374 / Cor.coef. Fo:Fc free: 0.9165 / SU R Cruickshank DPI: 0.145 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.148 / SU Rfree Blow DPI: 0.136 / SU Rfree Cruickshank DPI: 0.135
Details: GOL A1332, HOH B2208, HOH D2175 HAVE NO ALTERNATE CONFORMER AS THEY CORRESPOND TO ALTERNATE SIDE-CHAIN CONFORMERS IN THE PROTEIN CHAIN. THESE ARE RESPECTIVELY- TYR A 238, TYR B 238 AND TYR B 238.
RfactorNum. reflection% reflectionSelection details
Rfree0.2286 5671 5.1 %RANDOM
Rwork0.1884 ---
obs0.1904 112340 89.65 %-
Displacement parametersBiso mean: 28.18 Å2
Baniso -1Baniso -2Baniso -3
1-4.1642 Å20 Å2-0.6538 Å2
2---0.2728 Å20 Å2
3----3.8914 Å2
Refine analyzeLuzzati coordinate error obs: 0.293 Å
Refinement stepCycle: LAST / Resolution: 1.78→64.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10001 0 258 999 11258
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110731HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1414594HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3740SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes246HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1627HARMONIC5
X-RAY DIFFRACTIONt_it10731HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.56
X-RAY DIFFRACTIONt_other_torsion16.8
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1377SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies21HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact13777SEMIHARMONIC4
LS refinement shellResolution: 1.78→1.83 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2318 302 5.42 %
Rwork0.1945 5274 -
all0.1965 5576 -
obs--89.65 %
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)
10.60260.01620.23810.47830.0540.89350.09150.1043-0.13250.00310.008-0.06450.19790.1435-0.09950.17150.0139-0.11760.0828-0.037-0.125119.533-14.734515.4598
20.67390.0510.13990.62270.04170.6193-0.02-0.00970.0539-0.00570.01030.0492-0.068-0.04230.00970.1575-0.008-0.0920.08310.0072-0.1413-1.813810.063219.1344
30.8559-0.15130.06590.6819-0.110.6101-0.0161-0.09220.13190.01260-0.0764-0.12040.14660.01610.1324-0.0462-0.10180.1011-0.0354-0.178527.177215.282340.4339
40.4595-0.04110.09570.7066-0.07120.69940.0368-0.158-0.05480.08930.0420.0270.1302-0.0664-0.07880.154-0.0233-0.10410.13110.0387-0.152310.461-10.726950.4841
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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