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- PDB-5w8i: Crystal Structure of Lactate Dehydrogenase A in complex with inhi... -

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Basic information

Entry
Database: PDB / ID: 5w8i
TitleCrystal Structure of Lactate Dehydrogenase A in complex with inhibitor compound 23 and Zinc
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE / oxidoreductase inhibitor
Function / homology
Function and homology information


oxidoreductase complex / Pyruvate metabolism / L-lactate dehydrogenase / lactate metabolic process / L-lactate dehydrogenase activity / pyruvate metabolic process / substantia nigra development / glycolytic process / cadherin binding / mitochondrion ...oxidoreductase complex / Pyruvate metabolism / L-lactate dehydrogenase / lactate metabolic process / L-lactate dehydrogenase activity / pyruvate metabolic process / substantia nigra development / glycolytic process / cadherin binding / mitochondrion / extracellular exosome / identical protein binding / membrane / nucleus / 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-9YD / CITRIC ACID / MALONIC ACID / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 1.95 Å
AuthorsLukacs, C.M. / Abendroth, J.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH).
Authors: Rai, G. / Brimacombe, K.R. / Mott, B.T. / Urban, D.J. / Hu, X. / Yang, S.M. / Lee, T.D. / Cheff, D.M. / Kouznetsova, J. / Benavides, G.A. / Pohida, K. / Kuenstner, E.J. / Luci, D.K. / ...Authors: Rai, G. / Brimacombe, K.R. / Mott, B.T. / Urban, D.J. / Hu, X. / Yang, S.M. / Lee, T.D. / Cheff, D.M. / Kouznetsova, J. / Benavides, G.A. / Pohida, K. / Kuenstner, E.J. / Luci, D.K. / Lukacs, C.M. / Davies, D.R. / Dranow, D.M. / Zhu, H. / Sulikowski, G. / Moore, W.J. / Stott, G.M. / Flint, A.J. / Hall, M.D. / Darley-Usmar, V.M. / Neckers, L.M. / Dang, C.V. / Waterson, A.G. / Simeonov, A. / Jadhav, A. / Maloney, D.J.
History
DepositionJun 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 17, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 4, 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_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)149,51322
Polymers146,9394
Non-polymers2,57418
Water16,430912
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area25000 Å2
ΔGint-314 kcal/mol
Surface area41280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)166.840, 80.430, 119.620
Angle α, β, γ (deg.)90.000, 117.730, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
L-lactate dehydrogenase A chain / LDH-A / Cell proliferation-inducing gene 19 protein / LDH muscle subunit / LDH-M / Renal carcinoma ...LDH-A / Cell proliferation-inducing gene 19 protein / LDH muscle subunit / LDH-M / Renal carcinoma antigen NY-REN-59


Mass: 36734.672 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LDHA, PIG19 / Production host: Escherichia coli (E. coli) / References: UniProt: P00338, L-lactate dehydrogenase

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Non-polymers , 7 types, 930 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-9YD / 2-[3-(3,4-difluorophenyl)-5-hydroxy-1H-pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid


Mass: 323.275 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C13H7F2N3O3S
#4: Chemical
ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H8O7
#5: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-MLA / MALONIC ACID / DICARBOXYLIC ACID C3 / PROPANEDIOLIC ACID / METHANEDICARBOXYLIC ACID


Mass: 104.061 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H4O4
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 912 / 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: 2.34 Å3/Da / Density % sol: 47 %
Crystal growTemperature: 289 K / Method: vapor diffusion / pH: 6.8
Details: 24% PEG 3350, 200 mM Sodium Malonate, pH 6.8, 10% Glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Jan 27, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 102092 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 9.4 % / Biso Wilson estimate: 26.99 Å2 / Rmerge(I) obs: 0.083 / Net I/σ(I): 21.84
Reflection shellResolution: 1.95→2 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.556 / Mean I/σ(I) obs: 3.2 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementStarting model: IN-HOUSE APO SOLVED WITH MODEL 4JNK

4jnk


Resolution: 1.95→50 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.948 / SU B: 5.974 / SU ML: 0.086 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.136 / ESU R Free: 0.126
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.188 5091 5 %RANDOM
Rwork0.149 ---
obs0.151 102092 99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 68.62 Å2 / Biso mean: 21.13 Å2 / Biso min: 9.45 Å2
Baniso -1Baniso -2Baniso -3
1-0.32 Å2-0 Å2-0.3 Å2
2--0.09 Å20 Å2
3----0.06 Å2
Refinement stepCycle: final / Resolution: 1.95→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9973 0 152 912 11037
Biso mean--24.4 30.45 -
Num. residues----1315
LS refinement shellResolution: 1.95→2 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.254 367 -
Rwork0.209 7131 -
all-7498 -
obs--99.69 %
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)
10.08760.00230.00970.1920.1020.2389-0.00660.01320.00080.04680.0007-0.0132-0.08320.01720.00590.1121-0.0185-0.00290.0072-0.00090.003537.174317.207635.9765
20.1351-0.13070.03940.19820.03340.25520.00520.0012-0.01320.06390.0168-0.00040.02010.0115-0.02190.083-0.001-0.01370.03840.00390.005340.7713-15.034237.4657
30.16970.00970.06040.139-0.03510.14810.0078-0.01460.00580.02220.0170.0332-0.0038-0.1012-0.02480.0130.00640.0220.08020.02170.04185.4589-0.434328.4288
40.1561-0.17670.0430.2521-0.02440.20920.03030.0564-0.0085-0.0007-0.02520.0253-0.00040.021-0.00510.04330.0097-0.00210.06350.01480.024127.6297-5.04974.9164
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 507
2X-RAY DIFFRACTION2B1 - 507
3X-RAY DIFFRACTION3C1 - 507
4X-RAY DIFFRACTION4D1 - 507

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