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- PDB-9e0q: CryoEM structure of inducible Lysine decarboxylase from Hafnia al... -

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Entry
Database: PDB / ID: 9e0q
TitleCryoEM structure of inducible Lysine decarboxylase from Hafnia alvei D-hydrazino-Lysine analog at 2.3 Angstrom resolution
ComponentsLysine decarboxylase, inducible
KeywordsLYASE / L-Lysine decarboxylase / cadaverine / D-alpha-hydrazone inhibitor
Function / homology
Function and homology information


arginine decarboxylase activity / lysine decarboxylase / L-arginine catabolic process / pyridoxal phosphate binding / cytosol
Similarity search - Function
Orn/Lys/Arg decarboxylase, N-terminal / Ornithine/lysine/arginine decarboxylase / Orn/Lys/Arg decarboxylase, N-terminal domain / Orn/Lys/Arg decarboxylases family 1 pyridoxal-P attachment site. / Orn/Lys/Arg decarboxylase, major domain / Orn/Lys/Arg decarboxylase, C-terminal / Orn/Lys/Arg decarboxylase, C-terminal domain superfamily / Orn/Lys/Arg decarboxylase, major domain / Orn/Lys/Arg decarboxylase, C-terminal domain / Pyridoxal phosphate-dependent transferase, small domain ...Orn/Lys/Arg decarboxylase, N-terminal / Ornithine/lysine/arginine decarboxylase / Orn/Lys/Arg decarboxylase, N-terminal domain / Orn/Lys/Arg decarboxylases family 1 pyridoxal-P attachment site. / Orn/Lys/Arg decarboxylase, major domain / Orn/Lys/Arg decarboxylase, C-terminal / Orn/Lys/Arg decarboxylase, C-terminal domain superfamily / Orn/Lys/Arg decarboxylase, major domain / Orn/Lys/Arg decarboxylase, C-terminal domain / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
: / lysine decarboxylase
Similarity search - Component
Biological speciesHafnia alvei ATCC 51873 (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.3 Å
AuthorsDuhoo, Y. / Desfosses, A. / Gutsche, I. / Doukov, T.I. / Berkowitz, D.B.
Funding support France, United States, 4items
OrganizationGrant numberCountry
French National Research AgencyANR-10-INBS-0005-02 France
French National Research AgencyANR-17-EURE-0003 France
National Science Foundation (NSF, United States)NSF-2102705 United States
National Science Foundation (NSF, United States)NSF-2400333 United States
Citation
Journal: ACS Catal / Year: 2025
Title: α-Hydrazino Acids Inhibit Pyridoxal Phosphate-Dependent Decarboxylases via "Catalytically Correct" Ketoenamine Tautomers: A Special Motif for Chemical Biology and Drug Discovery?
Authors: Jonathan M Baine / Yoan Duhoo / Tzanko Doukov / Ambroise Desfosses / Giovanni Bisello / Matthew L Beio / Olivia Bauer / Massimiliano Perduca / Maria Bacia-Verloop / Mariarita Bertoldi / ...Authors: Jonathan M Baine / Yoan Duhoo / Tzanko Doukov / Ambroise Desfosses / Giovanni Bisello / Matthew L Beio / Olivia Bauer / Massimiliano Perduca / Maria Bacia-Verloop / Mariarita Bertoldi / Robert S Phillips / Irina Gutsche / David B Berkowitz /
Abstract: We present evidence that supports a 'correct hydrazone tautomer/Dunathan alignment model' for how α-hydrazino analogues of α-amino acids inhibit PLP enzymes. Described is the asymmetric synthesis ...We present evidence that supports a 'correct hydrazone tautomer/Dunathan alignment model' for how α-hydrazino analogues of α-amino acids inhibit PLP enzymes. Described is the asymmetric synthesis of l- and d-α-hydrazino acid l-lysine analogues and their inhibition of lysine decarboxylase (LdcI) via kinetic analysis, stopped-flow spectrophotometry, and cryo-EM. We describe a similar investigation of the important anti-Parkinsonism drug, carbidopa, with its human DOPA decarboxylase (hDdc) target. Evidence is consistent with these three hydrazino analogues forming the catalytically relevant ketoenamine PLP-hydrazone tautomer in their target active sites, with the α-carboxylate groups, though insulated, aligning with the PLP-π-system in a Dunathan-model-like orientation. High-resolution cryo-EM structures of the LdcI holoenzyme (pdb 9E0M-2.1Å) and LdcI-bound l- and d-hydrazones (pdb 9E0O-2.0 Å; pdb 9E0Q-2.3Å) and the first X-ray crystal structure of hDdc-bound carbidopa (pdb 9GNS-1.93Å) support this 'correct tautomer' model. These insights are expected to guide future PLP enzyme inhibitor development.
#1: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionOct 18, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 30, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Lysine decarboxylase, inducible
B: Lysine decarboxylase, inducible
C: Lysine decarboxylase, inducible
D: Lysine decarboxylase, inducible
E: Lysine decarboxylase, inducible
F: Lysine decarboxylase, inducible
G: Lysine decarboxylase, inducible
H: Lysine decarboxylase, inducible
I: Lysine decarboxylase, inducible
J: Lysine decarboxylase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)805,95620
Polymers802,05310
Non-polymers3,90310
Water13,097727
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Lysine decarboxylase, inducible


Mass: 80205.281 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hafnia alvei ATCC 51873 (bacteria) / Gene: HMPREF0454_03276
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: G9Y9L1
#2: Chemical
ChemComp-A1BD0 / (2R)-6-amino-2-[(2E)-2-({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methylidene)hydrazin-1-yl]hexanoic acid


Mass: 390.329 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C14H23N4O7P / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 727 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Inducible Lysine decarboxylase from Hafnia alvei with D-alpha-hydrazino-Lysine inhibitor
Type: COMPLEX
Details: Inducible Lysine decarboxylase from Hafnia alvei with D-alpha-hydrazino-Lysine inhibitor in ketoenamine form
Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Hafnia alvei ATCC 51873 (bacteria)
Source (recombinant)Organism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Plasmid: peT28+
Buffer solutionpH: 7.4
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
2PHENIX1.21.2_5419model refinement
13cryoSPARC3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: D5 (2x5 fold dihedral)
3D reconstructionResolution: 2.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 360000 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 13.23 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002957960
ELECTRON MICROSCOPYf_angle_d0.549478570
ELECTRON MICROSCOPYf_chiral_restr0.04278540
ELECTRON MICROSCOPYf_plane_restr0.004410190
ELECTRON MICROSCOPYf_dihedral_angle_d7.84267968

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