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- PDB-6sbu: X-ray Structure of Human LDHA with an Allosteric Inhibitor (Compo... -

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Basic information

Entry
Database: PDB / ID: 6sbu
TitleX-ray Structure of Human LDHA with an Allosteric Inhibitor (Compound 3)
ComponentsL-lactate dehydrogenase A chain
KeywordsOXIDOREDUCTASE / LDHA / OXIDOREDUCTASE INHIBITOR / ALLOSTERIC INHIBITOR
Function / homology
Function and homology information


L-lactate dehydrogenase / oxidoreductase complex / Pyruvate metabolism / lactate metabolic process / L-lactate dehydrogenase activity / pyruvate metabolic process / substantia nigra development / Regulation of pyruvate metabolism / glycolytic process / cadherin binding ...L-lactate dehydrogenase / oxidoreductase complex / Pyruvate metabolism / lactate metabolic process / L-lactate dehydrogenase activity / pyruvate metabolic process / substantia nigra development / Regulation of pyruvate metabolism / 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-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 domain superfamily
Similarity search - Domain/homology
Chem-L5N / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / L-lactate dehydrogenase A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.91 Å
AuthorsFriberg, A. / Puetter, V. / Nguyen, D. / Rehwinkel, H.
CitationJournal: Acs Omega / Year: 2020
Title: Structural Evidence for Isoform-Selective Allosteric Inhibition of Lactate Dehydrogenase A.
Authors: Friberg, A. / Rehwinkel, H. / Nguyen, D. / Putter, V. / Quanz, M. / Weiske, J. / Eberspacher, U. / Heisler, I. / Langer, G.
History
DepositionJul 22, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 10, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_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)298,14218
Polymers293,2848
Non-polymers4,85810
Water1,65792
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)149,0719
Polymers146,6424
Non-polymers2,4295
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area19740 Å2
ΔGint-124 kcal/mol
Surface area48030 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)149,0719
Polymers146,6424
Non-polymers2,4295
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area19690 Å2
ΔGint-122 kcal/mol
Surface area48080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.445, 143.853, 311.225
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14A
24E
15A
25F
16A
26G
17A
27H
18B
28C
19B
29D
110B
210E
111B
211F
112B
212G
113B
213H
114C
214D
115C
215E
116C
216F
117C
217G
118C
218H
119D
219E
120D
220F
121D
221G
122D
222H
123E
223F
124E
224G
125E
225H
126F
226G
127F
227H
128G
228H

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: PHE / End label comp-ID: PHE / Refine code: _ / Auth seq-ID: 2 - 332 / Label seq-ID: 2 - 332

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14AA
24EE
15AA
25FF
16AA
26GG
17AA
27HH
18BB
28CC
19BB
29DD
110BB
210EE
111BB
211FF
112BB
212GG
113BB
213HH
114CC
214DD
115CC
215EE
116CC
216FF
117CC
217GG
118CC
218HH
119DD
219EE
120DD
220FF
121DD
221GG
122DD
222HH
123EE
223FF
124EE
224GG
125EE
225HH
126FF
226GG
127FF
227HH
128GG
228HH

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28

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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: 36660.527 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LDHA, PIG19 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P00338, L-lactate dehydrogenase
#2: Chemical
ChemComp-L5N / 4-[[4-[(5-chloranylthiophen-2-yl)carbonylamino]-1,3-bis(oxidanylidene)isoindol-2-yl]methyl]benzoic acid


Mass: 440.856 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: C21H13ClN2O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NAI / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / NADH


Mass: 665.441 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H29N7O14P2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.99 Å3/Da / Density % sol: 58.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES pH 7.5-7.7, 4-8% PEG 8000, 20% ethylene glycol, and 10% acetonitrile
PH range: 7.5-7.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.975656 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.975656 Å / Relative weight: 1
ReflectionResolution: 2.91→50 Å / Num. obs: 77153 / % possible obs: 99 % / Redundancy: 4.4 % / CC1/2: 0.995 / Rrim(I) all: 0.156 / Net I/σ(I): 9.14
Reflection shellResolution: 2.91→3.09 Å / Redundancy: 4.6 % / Mean I/σ(I) obs: 1.85 / Num. unique obs: 12009 / CC1/2: 0.773 / Rrim(I) all: 1.078 / % possible all: 96.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
XSCALEdata scaling
PHASER2.5.6phasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4L4R

4l4r


Resolution: 2.91→48.8 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.926 / SU B: 19.564 / SU ML: 0.33 / Cross valid method: THROUGHOUT / ESU R Free: 0.379 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24447 2100 2.7 %RANDOM
Rwork0.20749 ---
obs0.20848 75038 98.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 63.2 Å2
Baniso -1Baniso -2Baniso -3
1-3.85 Å20 Å20 Å2
2--0.54 Å2-0 Å2
3----4.38 Å2
Refinement stepCycle: LAST / Resolution: 2.91→48.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms20320 0 328 92 20740
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.01321040
X-RAY DIFFRACTIONr_bond_other_d0.0010.01720383
X-RAY DIFFRACTIONr_angle_refined_deg1.4441.64928498
X-RAY DIFFRACTIONr_angle_other_deg1.1651.58647215
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.93352612
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.64723.431883
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.426153869
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.0111589
X-RAY DIFFRACTIONr_chiral_restr0.0510.22730
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0222886
X-RAY DIFFRACTIONr_gen_planes_other0.0010.023937
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.5156.44710484
X-RAY DIFFRACTIONr_mcbond_other4.5146.44710483
X-RAY DIFFRACTIONr_mcangle_it6.8519.67313078
X-RAY DIFFRACTIONr_mcangle_other6.859.67313079
X-RAY DIFFRACTIONr_scbond_it5.0197.110556
X-RAY DIFFRACTIONr_scbond_other57.110554
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.88610.41315414
X-RAY DIFFRACTIONr_long_range_B_refined10.11374.35222433
X-RAY DIFFRACTIONr_long_range_B_other10.11474.35222434
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A101870.04
12B101870.04
21A101920.04
22C101920.04
31A101760.04
32D101760.04
41A102140.04
42E102140.04
51A101880.04
52F101880.04
61A102140.03
62G102140.03
71A101860.04
72H101860.04
81B102290.03
82C102290.03
91B102470.03
92D102470.03
101B102260.03
102E102260.03
111B102550.03
112F102550.03
121B102260.03
122G102260.03
131B102480.03
132H102480.03
141C102000.04
142D102000.04
151C102210.03
152E102210.03
161C101990.04
162F101990.04
171C102350.03
172G102350.03
181C102270.03
182H102270.03
191D102190.03
192E102190.03
201D102250.04
202F102250.04
211D102120.03
212G102120.03
221D102590.03
222H102590.03
231E102160.03
232F102160.03
241E102330.03
242G102330.03
251E102370.03
252H102370.03
261F102160.04
262G102160.04
271F102240.04
272H102240.04
281G102270.03
282H102270.03
LS refinement shellResolution: 2.915→2.99 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.399 143 -
Rwork0.365 5132 -
obs--93.38 %

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