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- PDB-4m49: Lactate Dehydrogenase A in complex with a substituted pyrazine in... -

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Basic information

Entry
Database: PDB / ID: 4m49
TitleLactate Dehydrogenase A in complex with a substituted pyrazine inhibitor compound 18
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / dehydrogenase/reductase / nicotinamide adenine dinucleotide NADH / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


L-lactate dehydrogenase / oxidoreductase complex / L-lactate dehydrogenase (NAD+) activity / Pyruvate metabolism / lactate metabolic process / pyruvate metabolic process / substantia nigra development / Regulation of pyruvate metabolism / glycolytic process / cadherin binding ...L-lactate dehydrogenase / oxidoreductase complex / L-lactate dehydrogenase (NAD+) activity / Pyruvate metabolism / lactate metabolic process / pyruvate metabolic process / substantia nigra development / Regulation of pyruvate metabolism / glycolytic process / cadherin binding / mitochondrion / extracellular exosome / identical protein binding / nucleus / membrane / 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-22Y / LACTIC ACID / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.052 Å
AuthorsEigenbrot, C. / Ultsch, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Identification of 2-amino-5-aryl-pyrazines as inhibitors of human lactate dehydrogenase.
Authors: Fauber, B.P. / Dragovich, P.S. / Chen, J. / Corson, L.B. / Ding, C.Z. / Eigenbrot, C. / Giannetti, A.M. / Hunsaker, T. / Labadie, S. / Liu, Y. / Liu, Y. / Malek, S. / Peterson, D. / Pitts, K. ...Authors: Fauber, B.P. / Dragovich, P.S. / Chen, J. / Corson, L.B. / Ding, C.Z. / Eigenbrot, C. / Giannetti, A.M. / Hunsaker, T. / Labadie, S. / Liu, Y. / Liu, Y. / Malek, S. / Peterson, D. / Pitts, K. / Sideris, S. / Ultsch, M. / Vanderporten, E. / Wang, J. / Wei, B. / Yen, I. / Yue, Q.
History
DepositionAug 6, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 2, 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
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Category: atom_site / chem_comp_atom / chem_comp_bond
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2

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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)151,27518
Polymers146,4144
Non-polymers4,86114
Water8,827490
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area27340 Å2
ΔGint-214 kcal/mol
Surface area44240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)168.379, 81.821, 120.665
Angle α, β, γ (deg.)90.00, 117.65, 90.00
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: 36603.473 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, 504 molecules

#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-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#4: Chemical ChemComp-22Y / 3-(5-amino-6-{[(1R)-1-phenylethyl]amino}pyrazin-2-yl)-4-chlorobenzoic acid


Mass: 368.817 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C19H17ClN4O2
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-LAC / LACTIC ACID


Mass: 90.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H6O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 490 / 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: 2.51 Å3/Da / Density % sol: 51.08 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: PEG3350, HEPES, pH 7.2, VAPOR DIFFUSION, SITTING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 26, 2011
RadiationMonochromator: Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. all: 90543 / Num. obs: 90472 / % possible obs: 99.9 % / Observed criterion σ(F): 1 / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 35 Å2 / Rmerge(I) obs: 0.055 / Net I/σ(I): 22

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1I10

1i10


Resolution: 2.052→41.743 Å / SU ML: 0.16
Isotropic thermal model: individual atom isotropic thermal factors with TLS in 24 groups added for macromolecules
σ(F): 1.33 / Phase error: 27.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2237 545 0.6 %random
Rwork0.1713 ---
all0.1718 90543 --
obs0.1717 90472 99.52 %-
Solvent computationShrinkage radii: 0.98 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 43.675 Å2 / ksol: 0.301 e/Å3
Displacement parametersBiso mean: 50 Å2
Baniso -1Baniso -2Baniso -3
1-16.8705 Å2-0 Å2-2.1209 Å2
2---0.8395 Å2-0 Å2
3----16.0311 Å2
Refinement stepCycle: LAST / Resolution: 2.052→41.743 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10272 0 320 490 11082
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00710985
X-RAY DIFFRACTIONf_angle_d0.97214940
X-RAY DIFFRACTIONf_dihedral_angle_d17.9744371
X-RAY DIFFRACTIONf_chiral_restr0.0621727
X-RAY DIFFRACTIONf_plane_restr0.0031844
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0522-2.25870.29731300.241522207X-RAY DIFFRACTION99
2.2587-2.58550.29131400.201622447X-RAY DIFFRACTION100
2.5855-3.25720.24161260.179822557X-RAY DIFFRACTION100
3.2572-41.75190.19321490.149522716X-RAY DIFFRACTION100
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)
10.1422-0.1699-0.5190.25870.53721.2425-0.1203-0.37440.2501-0.340.2946-0.3398-0.28420.2746-0.17510.4092-0.0365-0.01670.51180.00240.404649.3996-2.70367.4744
20.1855-0.7439-0.09781.8184-0.02430.9962-0.03260.09280.11220.1529-0.0526-0.116-0.12580.14550.08930.3139-0.0601-0.02480.23240.02020.278347.29796.42329.0016
32.49410.01120.22652.37271.24014.446-0.1276-0.81960.15260.86530.1287-0.38020.5040.5654-0.02660.67-0.0746-0.1080.6164-0.03960.417152.43223.325540.2046
41.19040.0311-0.57020.3645-0.15891.3450.0098-0.10960.18420.3001-0.00740.0021-0.4456-0.0815-0.0140.54650.03610.00730.262-0.01620.305830.360220.667640.3594
51.19-0.38160.14350.82370.78071.1573-0.0821-0.33210.11870.27450.07460.0054-0.1603-0.17180.00180.51340.04810.00170.3371-0.01820.321129.72916.363445.2097
61.140.38220.66481.25280.42741.5967-0.0046-0.06590.49860.2262-0.02780.0554-0.64310.07450.03590.7036-0.01130.00120.2879-0.02990.405933.390232.802239.3507
71.9291-1.1653-1.34030.64860.70730.93940.0458-0.1845-0.160.6931-0.06020.31890.1021-0.4001-0.08150.6449-0.03090.11180.6354-0.00820.431910.57461.888750.2831
81.221-0.99420.03191.889-0.21340.7137-0.2277-0.3729-0.01950.47860.26330.1443-0.2102-0.3072-0.03510.42470.05750.05210.33030.02520.257132.9053-3.887846.8222
91.4587-0.64580.63641.4412-0.02031.32080.0223-0.2068-0.12270.39790.0524-0.1072-0.1999-0.093-0.08150.39710.0042-0.06850.26190.02420.247247.2266-16.223850.7073
100.576-0.31110.51290.9018-0.0332.11170.06370.0675-0.08960.05240.0106-0.06980.13360.1038-0.08240.2586-0.0175-0.02380.2456-0.00480.281946.7992-19.070728.5335
111.23650.28510.96841.60881.74794.25240.00370.11630.12810.10290.1858-0.47160.01510.6512-0.17670.2783-0.0216-0.08270.33370.02020.390858.218-10.885630.6842
121.2234-0.10720.85551.5210.38781.56790.00930.0333-0.24640.14270.131-0.01060.28770.0391-0.12050.2898-0.02730.02740.2411-0.00280.268343.0349-24.283534.4407
130.7609-1.38380.00372.5471-0.0326-0.0154-0.3767-0.0875-0.62410.19480.05030.86840.0862-0.06840.32570.6546-0.1486-0.06830.4550.05440.645427.3743-29.432629.1106
140.6143-0.7581-0.39810.95080.10591.76040.0533-0.0243-0.18580.03980.05980.08130.1262-0.0897-0.10230.235-0.06190.01380.35920.02750.372712.6756-12.77122.3132
154.1323-1.72661.7932.5632-0.41972.5086-0.11380.2117-0.2817-0.5743-0.0430.6878-0.033-0.66390.15710.3703-0.025-0.05450.76090.00710.5486-7.666-7.421124.1212
161.07980.53380.38761.03320.37761.2352-0.0287-0.08420.08620.1007-0.05580.3539-0.2844-0.55140.05870.34250.10990.07030.5377-0.00640.40655.05619.645431.8913
170.91140.50311.05844.15541.08471.96850.0665-0.36940.19930.0342-0.05111.0852-0.1906-0.7854-0.02620.49910.22170.16360.98610.01710.8057-11.50558.314335.4334
18-0.01320.49310.16764.361.34320.75360.13110.31620.4253-0.4779-0.01490.0372-0.77970.0628-0.09570.70840.0652-0.08070.44630.08750.450225.37727.818622.2878
191.3878-0.1402-0.78631.1878-0.07511.9323-0.0556-0.02820.03040.06980.09560.1949-0.3346-0.3084-0.040.32030.0353-0.00790.33010.02370.325519.92758.450710.7354
202.13010.91830.5362.8051.59923.82730.39980.4259-0.2953-0.4098-0.51590.68860.2711-0.55410.05270.3880.0834-0.16850.4968-0.07840.487521.15880.7235-8.8238
210.147-0.2195-0.03521.2028-0.44580.56740.04910.1135-0.076-0.0756-0.00950.11610.1134-0.0566-0.02760.2413-0.0438-0.02660.3231-0.01040.304232.2422-12.60945.675
223.004-2.1906-0.32172.73670.1670.69860.23760.466-0.6133-0.4093-0.18640.52380.3501-0.3369-0.02850.4757-0.0626-0.07740.5279-0.09520.47724.151-26.98396.1822
231.0676-0.16860.88570.9856-0.22661.04330.13240.15860.0057-0.1485-0.09810.0289-0.03280.1802-0.0060.26140.00180.01070.3251-0.00120.261536.0031-7.25834.9503
241.6035-1.42260.50435.9551-1.85673.30630.12440.2904-0.1237-0.7343-0.00520.15530.1599-0.3214-0.13070.51280.0608-0.06450.442-0.08440.333833.4826-13.9163-11.7348
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resseq 1:20)
2X-RAY DIFFRACTION2chain 'A' and (resseq 21:93)
3X-RAY DIFFRACTION3chain 'A' and (resseq 94:126)
4X-RAY DIFFRACTION4chain 'A' and (resseq 127:213)
5X-RAY DIFFRACTION5chain 'A' and (resseq 214:275)
6X-RAY DIFFRACTION6chain 'A' and (resseq 276:331)
7X-RAY DIFFRACTION7chain 'B' and (resseq 1:20)
8X-RAY DIFFRACTION8chain 'B' and (resseq 21:93)
9X-RAY DIFFRACTION9chain 'B' and (resseq 94:126)
10X-RAY DIFFRACTION10chain 'B' and (resseq 127:225)
11X-RAY DIFFRACTION11chain 'B' and (resseq 226:244)
12X-RAY DIFFRACTION12chain 'B' and (resseq 245:331)
13X-RAY DIFFRACTION13chain 'C' and (resseq 1:20)
14X-RAY DIFFRACTION14chain 'C' and (resseq 21:93)
15X-RAY DIFFRACTION15chain 'C' and (resseq 94:126)
16X-RAY DIFFRACTION16chain 'C' and (resseq 127:308)
17X-RAY DIFFRACTION17chain 'C' and (resseq 309:331)
18X-RAY DIFFRACTION18chain 'D' and (resseq 1:20)
19X-RAY DIFFRACTION19chain 'D' and (resseq 21:93)
20X-RAY DIFFRACTION20chain 'D' and (resseq 94:126)
21X-RAY DIFFRACTION21chain 'D' and (resseq 127:213)
22X-RAY DIFFRACTION22chain 'D' and (resseq 214:244)
23X-RAY DIFFRACTION23chain 'D' and (resseq 245:308)
24X-RAY DIFFRACTION24chain 'D' and (resseq 309:331)

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