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

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Basic information

Entry
Database: PDB / ID: 4ajh
Titlerat LDHA in complex with N-(2-methyl-1,3-benzothiazol-6-yl)-3-ureido- propanamide and 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 / 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-(4-BROMANYLPHENOXY)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: 1.93 Å
AuthorsTucker, J.A. / Brassington, C. / Hassall, G. / Watson, M. / Ward, R. / Tart, J. / Davies, G. / Greenwood, R. / Pearson, S. / Debreczeni, J.
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)148,01519
Polymers145,4534
Non-polymers2,56215
Water19,0781059
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area23570 Å2
ΔGint-115.4 kcal/mol
Surface area39200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.055, 81.656, 128.941
Angle α, β, γ (deg.)90.00, 96.11, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.77605, 0.09929, 0.62281), (0.09652, -0.9572, 0.27287), (0.62324, 0.27187, 0.73325)6.06123, -9.89934, -0.75023
2given(-0.77605, 0.09929, 0.62281), (0.09652, -0.9572, 0.27287), (0.62324, 0.27187, 0.73325)6.06123, -9.89934, -0.75023
3given(-0.97877, -0.202, 0.03474), (-0.20439, 0.94928, -0.23893), (0.01529, -0.24096, -0.97041)27.28703, 10.38309, 61.26622

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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: MUSCLE / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): STAR / References: UniProt: P04642, L-lactate dehydrogenase

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Non-polymers , 5 types, 1074 molecules

#2: Chemical
ChemComp-MLI / MALONATE ION


Mass: 102.046 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H2O4
#3: 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
#4: Chemical ChemComp-2B4 / 2-(4-BROMANYLPHENOXY)PROPANEDIOIC ACID


Mass: 275.053 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H7BrO5
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1059 / 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 12, 2010 / Details: VARIMAXHF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.93→128.21 Å / Num. obs: 88736 / % possible obs: 92.3 % / Observed criterion σ(I): 2 / Redundancy: 3.4 % / Biso Wilson estimate: 21.9 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 11
Reflection shellResolution: 1.93→2.03 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 1.9 / % possible all: 64.8

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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: 1.93→64.1 Å / Cor.coef. Fo:Fc: 0.9513 / Cor.coef. Fo:Fc free: 0.9349 / SU R Cruickshank DPI: 0.152 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.159 / SU Rfree Blow DPI: 0.135 / SU Rfree Cruickshank DPI: 0.133
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY.
RfactorNum. reflection% reflectionSelection details
Rfree0.1889 4448 5.02 %RANDOM
Rwork0.1515 ---
obs0.1533 88643 92.06 %-
Displacement parametersBiso mean: 25.18 Å2
Baniso -1Baniso -2Baniso -3
1-0.4688 Å20 Å25.0607 Å2
2---3.8803 Å20 Å2
3---3.4115 Å2
Refine analyzeLuzzati coordinate error obs: 0.203 Å
Refinement stepCycle: LAST / Resolution: 1.93→64.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9988 0 167 1059 11214
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110371HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0914083HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3590SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes240HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1524HARMONIC5
X-RAY DIFFRACTIONt_it10371HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.37
X-RAY DIFFRACTIONt_other_torsion16.11
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1364SEMIHARMONIC5
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_contact13375SEMIHARMONIC4
LS refinement shellResolution: 1.93→1.98 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2444 208 5.07 %
Rwork0.2053 3892 -
all0.2072 4100 -
obs--92.06 %
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)
10.33350.04420.17980.31050.04680.79160.04240.0251-0.0476-0.02160.0195-0.05480.13890.0867-0.0618-0.01470.0086-0.0132-0.0433-0.0198-0.029320.0825-14.695215.0731
20.36010.02820.18210.3129-0.01560.3596-0.031-0.03910.04820.00210.00680.042-0.0573-0.07090.0243-0.00130.0065-0.0006-0.0143-0.0075-0.036-1.572110.310918.7575
30.55730.0110.20930.3508-0.080.4864-0.018-0.10470.08320.0205-0.0141-0.0328-0.08080.0580.0321-0.0244-0.0165-0.0003-0.0016-0.0332-0.054827.541315.397740.3036
40.37830.08090.11220.25720.0240.52980.0689-0.2039-0.06470.0901-0.03340.00880.12-0.0899-0.0354-0.0173-0.0446-0.01320.05490.0414-0.079911.044-11.176350.4468
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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