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- PDB-4ajl: rat LDHA in complex with 3-(ethylcarbamoylamino)-N-(2-methyl-1,3-... -

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Basic information

Entry
Database: PDB / ID: 4ajl
Titlerat LDHA in complex with 3-(ethylcarbamoylamino)-N-(2-methyl-1,3- benzothiazol-6-yl)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 / sperm fibrous sheath / pyruvate catabolic process / oxidoreductase complex / : / lactate metabolic process / L-lactate dehydrogenase / L-lactate dehydrogenase activity / NAD metabolic process ...lactate dehydrogenase activity / Pyruvate metabolism / sperm fibrous sheath / pyruvate catabolic process / oxidoreductase complex / : / lactate metabolic process / L-lactate dehydrogenase / L-lactate dehydrogenase activity / NAD metabolic process / pyruvate metabolic process / glucose catabolic process to lactate via pyruvate / 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
Chem-88W / MALONATE ION / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.77 Å
AuthorsTucker, J.A. / Brassington, C. / Hassall, G. / Vogtherr, M. / Ward, R. / Tart, J. / Davies, G. / Addie, M. / Ferguson, A.
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

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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)148,12623
Polymers145,4534
Non-polymers2,67319
Water21,5281195
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area25070 Å2
ΔGint-107.1 kcal/mol
Surface area40050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.289, 81.842, 129.023
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(-0.77696, 0.09765, 0.62193), (0.09512, -0.95835, 0.2693), (0.62232, 0.26839, 0.73531)6.01221, -9.90214, -0.72766
2given(-0.77696, 0.09765, 0.62193), (0.09512, -0.95835, 0.2693), (0.62232, 0.26839, 0.73531)6.01221, -9.90214, -0.72766
3given(-0.77696, 0.09765, 0.62193), (0.09512, -0.95835, 0.2693), (0.62232, 0.26839, 0.73531)6.01221, -9.90214, -0.72766
4given(-0.97876, -0.20239, 0.03252), (-0.20431, 0.95025, -0.23513), (0.01669, -0.23679, -0.97142)27.25078, 10.27218, 61.26928

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Components

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Protein , 1 types, 4 molecules ABCD

#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: MUSCLESkeletal 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 , 5 types, 1214 molecules

#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical
ChemComp-88W / N~3~-(ethylcarbamoyl)-N-(2-methyl-1,3-benzothiazol-6-yl)-beta-alaninamide / 3-(ETHYLCARBAMOYLAMINO)-N-(2-METHYL-1,3-BENZOTHIAZOL-6-


Mass: 306.383 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H18N4O2S
#4: Chemical
ChemComp-MLI / MALONATE ION / Malonic acid


Mass: 102.046 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H2O4
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1195 / 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: Jun 15, 2010 / Details: VARIMAXHF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.77→128.27 Å / Num. obs: 100915 / % possible obs: 80.5 % / Observed criterion σ(I): 2 / Redundancy: 3.2 % / Biso Wilson estimate: 19.57 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 13.4
Reflection shellResolution: 1.77→1.87 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 1.5 / % possible all: 22.2

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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: 1.77→25.1 Å / Cor.coef. Fo:Fc: 0.9589 / Cor.coef. Fo:Fc free: 0.9394 / SU R Cruickshank DPI: 0.124 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.13 / SU Rfree Blow DPI: 0.119 / SU Rfree Cruickshank DPI: 0.117
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
Rfree0.1828 5089 5.05 %RANDOM
Rwork0.1425 ---
obs0.1445 100840 80.39 %-
Displacement parametersBiso mean: 20.55 Å2
Baniso -1Baniso -2Baniso -3
1--0.0705 Å20 Å23.1658 Å2
2---1.6357 Å20 Å2
3---1.7062 Å2
Refine analyzeLuzzati coordinate error obs: 0.179 Å
Refinement stepCycle: LAST / Resolution: 1.77→25.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10055 0 180 1195 11430
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110475HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0514193HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3705SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes242HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1561HARMONIC5
X-RAY DIFFRACTIONt_it10475HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.49
X-RAY DIFFRACTIONt_other_torsion15.38
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1368SEMIHARMONIC5
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_contact13670SEMIHARMONIC4
LS refinement shellResolution: 1.77→1.82 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2797 55 4.02 %
Rwork0.2652 1312 -
all0.2658 1367 -
obs--80.39 %
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)
10.32540.06230.11030.2855-0.00410.53940.03650.0315-0.0644-0.00920.0073-0.05060.10650.0629-0.0438-0.02170.0081-0.011-0.0502-0.0138-0.022819.979-14.713915.1269
20.26880.05290.12230.2407-0.02260.3209-0.0263-0.01690.03140.00830.00630.0265-0.0486-0.06470.02-0.01840.0070.0011-0.0296-0.0026-0.027-1.65110.108218.9204
30.42640.02520.09120.3952-0.05250.4412-0.001-0.06960.04980.0138-0.0177-0.0288-0.05790.07880.0187-0.0449-0.02440.0021-0.0183-0.0204-0.050227.476515.401540.3821
40.34530.06810.04820.26540.02310.44490.0547-0.1586-0.04580.0799-0.02830.02070.0841-0.0607-0.0264-0.0365-0.0356-0.00960.01410.0315-0.069610.948-11.200950.3923
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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