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- PDB-5w8l: Crystal Structure of Lactate Dehydrogenase A in complex with inhi... -

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Basic information

Entry
Database: PDB / ID: 5w8l
TitleCrystal Structure of Lactate Dehydrogenase A in complex with inhibitor compound 59 and NADH
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 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-9YA / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsDavies, D.R. / 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)152,69025
Polymers146,9394
Non-polymers5,75121
Water21,2761181
1
A: L-lactate dehydrogenase A chain
C: L-lactate dehydrogenase A chain
hetero molecules

A: L-lactate dehydrogenase A chain
C: L-lactate dehydrogenase A chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,87628
Polymers146,9394
Non-polymers5,93824
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565-x,-y+1,z1
Buried area28990 Å2
ΔGint-122 kcal/mol
Surface area42120 Å2
MethodPISA
2
D: L-lactate dehydrogenase A chain
hetero molecules

D: L-lactate dehydrogenase A chain
hetero molecules

B: L-lactate dehydrogenase A chain
hetero molecules

B: L-lactate dehydrogenase A chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,50422
Polymers146,9394
Non-polymers5,56518
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,-y,z1
crystal symmetry operation3_445-x-1/2,y-1/2,-z1
crystal symmetry operation4_455x-1/2,-y+1/2,-z1
Buried area27720 Å2
ΔGint-137 kcal/mol
Surface area42020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)135.340, 95.340, 121.720
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-727-

HOH

21B-723-

HOH

31B-786-

HOH

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Components

#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
#2: Chemical
ChemComp-NAI / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / NADH


Mass: 665.441 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H29N7O14P2
#3: Chemical
ChemComp-9YA / 2-{3-([1,1'-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-[(4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid


Mass: 570.682 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C30H26N4O4S2
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1181 / 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: 2.68 Å3/Da / Density % sol: 54.13 %
Crystal growTemperature: 289 K / Method: vapor diffusion / pH: 6
Details: 8% PEG 8000, 100 mM Cacodylate, pH 6.0, 200 mM NaCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 9, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 114689 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 6.26 % / Biso Wilson estimate: 21.47 Å2 / Rmerge(I) obs: 0.122 / Net I/σ(I): 10.06
Reflection shellResolution: 1.95→2 Å / Rmerge(I) obs: 0.505 / Mean I/σ(I) obs: 3.31 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: proprietary structure of the same target

Resolution: 1.95→47.97 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 16.96
RfactorNum. reflection% reflection
Rfree0.176 2057 1.79 %
Rwork0.147 --
obs-114671 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 93.72 Å2 / Biso mean: 27.5114 Å2 / Biso min: 11.27 Å2
Refinement stepCycle: final / Resolution: 1.95→47.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10114 0 388 1193 11695
Biso mean--25.68 36.27 -
Num. residues----1324
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00610832
X-RAY DIFFRACTIONf_angle_d0.90714750
X-RAY DIFFRACTIONf_chiral_restr0.0541713
X-RAY DIFFRACTIONf_plane_restr0.0051827
X-RAY DIFFRACTIONf_dihedral_angle_d16.8296423
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.95-1.99530.22761360.185774417577100
1.9953-2.04520.24451260.180874517577100
2.0452-2.10050.20931390.168874187557100
2.1005-2.16240.19851340.158474937627100
2.1624-2.23210.23321450.157774467591100
2.2321-2.31190.17061440.155774787622100
2.3119-2.40450.18611230.14874747597100
2.4045-2.51390.19771300.14975377667100
2.5139-2.64640.19491400.152174657605100
2.6464-2.81220.17761490.147775177666100
2.8122-3.02930.21071390.150375057644100
3.0293-3.33410.14981180.14877515763399
3.3341-3.81640.16561310.13587567769899
3.8164-4.80760.12911690.11987536770599
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)
11.2052-0.04611.09530.0088-0.00671.1816-0.1997-0.5472-0.20510.15060.13660.10370.06230.17330.11320.2947-0.061-0.03510.26140.11590.304119.483939.3661-27.2272
21.002-0.1239-0.59180.1819-0.04540.8567-0.0198-0.0424-0.122-0.0422-0.04710.01430.12750.0240.01680.1841-0.05350.00480.1013-0.00040.172-6.715928.1871-33.3206
30.1661-0.07210.00040.6997-0.31440.55060.0069-0.0175-0.0008-0.0755-0.03920.16050.0418-0.19150.03620.1539-0.0545-0.02980.1764-0.03770.1963-23.69541.3564-40.6113
41.3802-1.68511.22183.9767-2.89343.0872-0.0451-0.14930.01530.16940.02510.0899-0.0169-0.250.04160.1557-0.1181-0.01480.3102-0.04770.2641-34.941133.8675-29.9736
50.27540.2346-0.2162.2055-1.34921.26280.00270.07590.0161-0.67980.04850.2625-0.1452-0.14950.06610.2208-0.0386-0.08870.29610.03870.2424-3.348768.4666-5.4842
60.4471-0.15580.21640.98470.63690.9198-0.0874-0.0683-0.0602-0.01640.0710.124-0.0722-0.1198-0.01070.11760.0085-0.00210.19680.01910.1632-20.214245.8280.2778
70.726-0.22740.2670.3789-0.11860.4861-0.0832-0.1048-0.17610.00490.08520.08610.1603-0.05240.00950.168-0.00450.0420.18020.0390.2079-11.834326.1667.86
81.3146-0.67430.65032.6963-1.1582.1514-0.10720.1961-0.1256-0.1122-0.01150.14160.2258-0.01260.06240.2642-0.08850.0130.15960.03370.3221-21.775917.3689-2.6312
90.340.02690.44060.01470.05960.80750.07430.4203-0.2586-0.294-0.06970.08020.0709-0.2180.04340.45390.011-0.14520.2896-0.05480.2952-20.629251.1994-67.2739
100.894-0.2215-0.43680.30850.37740.70980.04360.0514-0.111-0.2253-0.05950.10140.1028-0.0890.01510.3164-0.0117-0.02760.1207-0.03310.1685-5.012928.1744-61.0392
110.47820.12380.02380.71040.13370.55130.02230.0667-0.0848-0.177-0.0574-0.12520.16370.13870.04480.25240.03820.06290.13350.01650.19216.310329.4083-53.5362
123.07730.77551.87261.31470.90272.4658-0.04070.195-0.2098-0.39450.0282-0.20760.09090.2441-0.04450.45160.12470.11130.2378-0.02620.278921.295517.0348-64.0518
130.08480.03240.09310.43760.4180.9036-0.01950.3513-0.0195-0.4440.0027-0.19290.04880.170.07080.2904-0.12660.12220.495-0.14680.3468-66.0654-21.0823-34.268
140.23130.2246-0.3011.1337-0.64190.8501-0.12360.1953-0.0489-0.10270.0742-0.15820.10230.02460.02590.1658-0.09870.03020.3338-0.03850.1726-47.5551-0.3822-27.989
150.6461-0.1597-0.35270.4073-0.07310.317-0.11660.17870.1591-0.03060.1002-0.0376-0.09560.0210.01840.1673-0.1068-0.03890.27280.04970.1857-53.847820.1553-20.853
161.8941-0.4344-1.08681.53021.09661.7769-0.07750.1641-0.0098-0.12230.03760.0096-0.07-0.0223-0.03490.1983-0.1846-0.04330.34310.07350.2395-42.702128.0587-31.2907
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 126 )A21 - 126
3X-RAY DIFFRACTION3chain 'A' and (resid 127 through 308 )A127 - 308
4X-RAY DIFFRACTION4chain 'A' and (resid 309 through 331 )A309 - 331
5X-RAY DIFFRACTION5chain 'B' and (resid 1 through 20 )B1 - 20
6X-RAY DIFFRACTION6chain 'B' and (resid 21 through 126 )B21 - 126
7X-RAY DIFFRACTION7chain 'B' and (resid 127 through 308 )B127 - 308
8X-RAY DIFFRACTION8chain 'B' and (resid 309 through 331 )B309 - 331
9X-RAY DIFFRACTION9chain 'C' and (resid 1 through 20 )C1 - 20
10X-RAY DIFFRACTION10chain 'C' and (resid 21 through 126 )C21 - 126
11X-RAY DIFFRACTION11chain 'C' and (resid 127 through 308 )C127 - 308
12X-RAY DIFFRACTION12chain 'C' and (resid 309 through 331 )C309 - 331
13X-RAY DIFFRACTION13chain 'D' and (resid 1 through 20 )D1 - 20
14X-RAY DIFFRACTION14chain 'D' and (resid 21 through 126 )D21 - 126
15X-RAY DIFFRACTION15chain 'D' and (resid 127 through 308 )D127 - 308
16X-RAY DIFFRACTION16chain 'D' and (resid 309 through 331 )D309 - 331

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