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- PDB-5w8h: Crystal Structure of Lactate Dehydrogenase A in complex with inhi... -

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Basic information

Entry
Database: PDB / ID: 5w8h
TitleCrystal Structure of Lactate Dehydrogenase A in complex with inhibitor compound 11
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-9Y1 / ACETATE ION / MALONIC ACID / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsLukacs, C.M. / Dranow, D.M.
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 1.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)150,19821
Polymers146,9394
Non-polymers3,26017
Water17,781987
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area23270 Å2
ΔGint-139 kcal/mol
Surface area42690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)167.730, 81.210, 120.650
Angle α, β, γ (deg.)90.000, 118.220, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-809-

HOH

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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 , 6 types, 1004 molecules

#2: Chemical
ChemComp-9Y1 / 2-[3-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid


Mass: 357.283 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C14H7F4N3O2S
#3: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: 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
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 987 / 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: 2.38 Å3/Da / Density % sol: 48.3 %
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: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97949 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 131874 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 3.63 % / Biso Wilson estimate: 19.46 Å2 / Rmerge(I) obs: 0.075 / Net I/σ(I): 11.38
Reflection shellResolution: 1.8→1.85 Å / Redundancy: 3.68 % / Rmerge(I) obs: 0.525 / Mean I/σ(I) obs: 2.9 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: proprietary structure of the same target

Resolution: 1.8→48.17 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / Phase error: 17.67
RfactorNum. reflection% reflection
Rfree0.181 6602 5.01 %
Rwork0.147 --
obs0.148 131863 99.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 96.89 Å2 / Biso mean: 24.5716 Å2 / Biso min: 7.8 Å2
Refinement stepCycle: final / Resolution: 1.8→48.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10014 0 215 987 11216
Biso mean--44.9 34.9 -
Num. residues----1320
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01210752
X-RAY DIFFRACTIONf_angle_d1.25914676
X-RAY DIFFRACTIONf_chiral_restr0.0661705
X-RAY DIFFRACTIONf_plane_restr0.0061864
X-RAY DIFFRACTIONf_dihedral_angle_d15.3253995
LS refinement shellResolution: 1.8→1.82 Å / Rfactor Rfree error: 0 / Total num. of bins used: 30
RfactorNum. reflection% reflection
Rfree0.266 200 -
Rwork0.215 4136 -
all-4336 -
obs--100 %
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)
10.7925-0.767-0.40090.84350.58230.55340.1312-0.14320.4728-0.32070.1281-0.6559-0.35780.19360.03310.2293-0.0050.03670.30660.00980.222949.1855-3.26887.321
20.7948-0.204-0.40232.2284-0.26160.6113-0.0134-0.04590.09960.12330.0175-0.1873-0.17410.226-0.00430.1604-0.0646-0.01870.1256-0.0010.098547.222914.009132.2516
31.0322-0.0344-0.01040.5024-0.05920.4313-0.0409-0.18840.06970.18590.04150.03-0.2224-0.033-0.0020.23680.03320.02510.1156-0.01670.13226.640417.179243.7225
40.41870.06630.27750.5333-0.11340.385-0.03580.05120.37260.13740.01740.1324-0.4756-0.00540.00230.4124-0.02580.0220.0984-0.03860.239432.367232.122138.5429
50.2757-0.35240.17490.55190.04970.25180.0114-0.1267-0.10040.07890.00410.1979-0.0926-0.18070.00020.18630.02070.03470.17990.00290.149222.5125-1.496945.455
60.3359-0.2399-0.31930.98790.05440.3138-0.0285-0.14110.01520.24740.03770.113-0.0983-0.0408-00.1550.00720.02030.13750.00690.129230.9756-3.703947.7843
70.5463-0.14310.330.4148-0.10231.47940.0184-0.0382-0.06430.0970.0057-0.05060.00880.0262-0.00030.0865-0.0043-0.00820.0636-0.00150.101543.6501-18.011742.2616
80.5539-0.1841-0.06790.40760.11241.40870.01030.0634-0.06630.01330.0045-0.05840.07790.13710.00190.08220.0146-0.01560.0948-0.00520.102546.5398-18.990827.4787
90.3488-0.0912-0.15010.18970.22640.3674-0.0324-0.0918-0.21440.10450.1062-0.01230.2466-0.06040.00760.1881-0.0137-0.0160.14470.0070.211420.0622-18.918424.8311
100.5123-0.2815-0.51120.43680.06470.6857-0.0380.0321-0.202-0.04390.04330.07150.1587-0.1267-00.1197-0.0196-0.01860.150.02710.197312.6477-15.288321.5799
110.80630.50670.07750.8740.04580.5529-0.03930.04010.1133-0.08810.07190.2071-0.1485-0.21650.00020.13730.05990.00830.20340.03310.18583.28846.179628.0448
120.51530.43060.11450.37140.14680.62250.0547-0.2580.09190.1965-0.00590.2687-0.1946-0.42640.00590.15340.10410.0550.3310.02180.2845-5.29326.359438.2344
130.271-0.1172-0.05170.0948-0.00730.5565-0.06570.10320.19630.09790.11570.0416-0.37160.01140.00450.25980.01920.00760.11130.02940.197622.047515.096616.776
140.8433-0.3659-0.42050.78370.08631.15920.05990.09950.0169-0.0441-0.03710.1031-0.1442-0.0719-0.00010.1065-0.0037-0.01740.1310.0320.127222.46354.95011.3275
150.52790.04310.13950.6885-0.04510.65230.0490.0979-0.0902-0.08410.03290.14360.1716-0.011-00.10340.0089-0.01690.1239-0.00390.12932.4203-18.20729.1136
160.9826-0.51220.04860.87580.12421.41020.07350.221-0.1938-0.085-0.0780.0850.1542-0.02650.0030.12830.0168-0.01520.1803-0.02790.119932.2168-13.78221.9727
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 20 )A1 - 20
2X-RAY DIFFRACTION2chain 'A' and (resid 21 through 150 )A21 - 150
3X-RAY DIFFRACTION3chain 'A' and (resid 151 through 275 )A151 - 275
4X-RAY DIFFRACTION4chain 'A' and (resid 276 through 331 )A276 - 331
5X-RAY DIFFRACTION5chain 'B' and (resid 1 through 41 )B1 - 41
6X-RAY DIFFRACTION6chain 'B' and (resid 42 through 93 )B42 - 93
7X-RAY DIFFRACTION7chain 'B' and (resid 94 through 177 )B94 - 177
8X-RAY DIFFRACTION8chain 'B' and (resid 178 through 308 )B178 - 308
9X-RAY DIFFRACTION9chain 'C' and (resid 1 through 40 )C1 - 40
10X-RAY DIFFRACTION10chain 'C' and (resid 41 through 93 )C41 - 93
11X-RAY DIFFRACTION11chain 'C' and (resid 94 through 275)C94 - 275
12X-RAY DIFFRACTION12chain 'C' and (resid 276 through 331 )C276 - 331
13X-RAY DIFFRACTION13chain 'D' and (resid 1 through 40 )D1 - 40
14X-RAY DIFFRACTION14chain 'D' and (resid 41 through 150 )D41 - 150
15X-RAY DIFFRACTION15chain 'D' and (resid 151 through 213 )D151 - 213
16X-RAY DIFFRACTION16chain 'D' and (resid 214 through 331)D214 - 331

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