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- PDB-4i9n: Crystal structure of rabbit LDHA in complex with AP28161 and AP28122 -

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Basic information

Entry
Database: PDB / ID: 4i9n
TitleCrystal structure of rabbit LDHA in complex with AP28161 and AP28122
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / cancer / fragment / inhibitor / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


L-lactate dehydrogenase / L-lactate dehydrogenase (NAD+) activity / lactate metabolic process / cytoplasm
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-1E5 / Chem-1E6 / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsZhou, T. / Kohlmann, A. / Stephan, Z.G. / Li, F. / Commodore, L. / Greenfield, M.T. / Shakespeare, W.C. / Zhu, X. / Dalgarno, D.C.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors.
Authors: Kohlmann, A. / Zech, S.G. / Li, F. / Zhou, T. / Squillace, R.M. / Commodore, L. / Greenfield, M.T. / Lu, X. / Miller, D.P. / Huang, W.S. / Qi, J. / Thomas, R.M. / Wang, Y. / Zhang, S. / ...Authors: Kohlmann, A. / Zech, S.G. / Li, F. / Zhou, T. / Squillace, R.M. / Commodore, L. / Greenfield, M.T. / Lu, X. / Miller, D.P. / Huang, W.S. / Qi, J. / Thomas, R.M. / Wang, Y. / Zhang, S. / Dodd, R. / Liu, S. / Xu, R. / Xu, Y. / Miret, J.J. / Rivera, V. / Clackson, T. / Shakespeare, W.C. / Zhu, X. / Dalgarno, D.C.
History
DepositionDec 5, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 23, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2013Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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 / _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
E: L-lactate dehydrogenase A chain
F: L-lactate dehydrogenase A chain
G: L-lactate dehydrogenase A chain
H: L-lactate dehydrogenase A chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)297,72424
Polymers291,8518
Non-polymers5,87316
Water5,639313
1
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)148,86212
Polymers145,9264
Non-polymers2,9368
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area21370 Å2
ΔGint-125 kcal/mol
Surface area44170 Å2
MethodPISA
2
E: L-lactate dehydrogenase A chain
F: L-lactate dehydrogenase A chain
G: L-lactate dehydrogenase A chain
H: L-lactate dehydrogenase A chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)148,86212
Polymers145,9264
Non-polymers2,9368
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area21140 Å2
ΔGint-125 kcal/mol
Surface area44580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.040, 139.815, 138.934
Angle α, β, γ (deg.)90.000, 94.570, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
L-lactate dehydrogenase A chain / Lactate dehydrogenase A / LDHA / LDH-A / LDH muscle subunit / LDH-M


Mass: 36481.375 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P13491, L-lactate dehydrogenase
#2: Chemical
ChemComp-1E6 / 6-({2-[(5-chloro-4-{[(2S)-2,3-dihydroxypropyl]oxy}-2-methoxyphenyl)amino]-2-oxoethyl}sulfanyl)pyridine-3-carboxylic acid


Mass: 442.871 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C18H19ClN2O7S
#3: Chemical
ChemComp-1E5 / 6-[3-(carboxymethoxy)-5-fluorophenyl]pyridine-3-carboxylic acid


Mass: 291.231 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C14H10FNO5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 313 / 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: 2.79 Å3/Da / Density % sol: 55.88 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.1 M Tris, pH 8.0, 30% PEG550 MME, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Feb 8, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. all: 141773 / Num. obs: 133852 / % possible obs: 94.4 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellHighest resolution: 2.35 Å

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT3.11data extraction
StructureStudiodata collection
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1I10

1i10


Resolution: 2.35→50 Å / Occupancy max: 1 / Occupancy min: 0.5 / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2635 6381 4.8 %RANDOM
Rwork0.2201 119560 --
all-141773 --
obs-125941 94.7 %-
Displacement parametersBiso max: 96.32 Å2 / Biso mean: 30.9829 Å2 / Biso min: 3.65 Å2
Baniso -1Baniso -2Baniso -3
1-0.143 Å20 Å2-0.014 Å2
2---0.056 Å20 Å2
3----0.086 Å2
Refinement stepCycle: LAST / Resolution: 2.35→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms20239 0 400 313 20952
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.2991.5
X-RAY DIFFRACTIONc_scbond_it1.972
X-RAY DIFFRACTIONc_mcangle_it2.0932
X-RAY DIFFRACTIONc_scangle_it2.7562.5
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2dna-rna_rep.param
X-RAY DIFFRACTION3water_rep.param
X-RAY DIFFRACTION4ion.param
X-RAY DIFFRACTION5161_D.param
X-RAY DIFFRACTION6122_D.param

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