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- EMDB-47364: CryoEM structure of inducible Lysine decarboxylase from Hafnia al... -

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Basic information

Entry
Database: EMDB / ID: EMD-47364
TitleCryoEM structure of inducible Lysine decarboxylase from Hafnia alvei L-hydrazino-Lysine analog at 2.04 Angstrom resolution
Map datasharpenned
Sample
  • Complex: Inducible Lysine decarboxylase from Hafnia alvei with bound L-hydrazino-lysine inhibitor
    • Protein or peptide: Lysine decarboxylase, inducible
  • Ligand: (2R)-6-amino-2-[(2E)-2-({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methylidene)hydrazin-1-yl]hexanoic acid
  • Ligand: water
KeywordsL-Lysine decarboxylase / cadaverine / alpha-hydrazone inhibitor / LYASE
Function / homology
Function and homology information


arginine decarboxylase activity / 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, inducible
Similarity search - Component
Biological speciesHafnia alvei ATCC 51873 (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.0 Å
AuthorsDuhoo Y / Desfosses A / Gutsche I / Doukov TI / Berkowitz DB
Funding support France, United States, 4 items
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
CitationJournal: 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.
History
DepositionOct 18, 2024-
Header (metadata) releaseJun 4, 2025-
Map releaseJun 4, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47364.png

Downloads & links

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Map

FileDownload / File: emd_47364.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpenned
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.65 Å/pix.
x 512 pix.
= 330.24 Å		0.65 Å/pix.
x 512 pix.
= 330.24 Å		0.65 Å/pix.
x 512 pix.
= 330.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.645 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.165
Minimum - Maximum-2.6400664 - 5.2216773
Average (Standard dev.)0.000000000000324 (±0.11621186)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 330.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: halfA

Fileemd_47364_half_map_1.map
AnnotationhalfA
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: halfB

Fileemd_47364_half_map_2.map
AnnotationhalfB
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Inducible Lysine decarboxylase from Hafnia alvei with bound L-hyd...

EntireName: Inducible Lysine decarboxylase from Hafnia alvei with bound L-hydrazino-lysine inhibitor
Components
  • Complex: Inducible Lysine decarboxylase from Hafnia alvei with bound L-hydrazino-lysine inhibitor
    • Protein or peptide: Lysine decarboxylase, inducible
  • Ligand: (2R)-6-amino-2-[(2E)-2-({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methylidene)hydrazin-1-yl]hexanoic acid
  • Ligand: water

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Supramolecule #1: Inducible Lysine decarboxylase from Hafnia alvei with bound L-hyd...

SupramoleculeName: Inducible Lysine decarboxylase from Hafnia alvei with bound L-hydrazino-lysine inhibitor
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: Enzyme with bound L-hydrazino-lysine inhibitor
Source (natural)Organism: Hafnia alvei ATCC 51873 (bacteria)

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Macromolecule #1: Lysine decarboxylase, inducible

MacromoleculeName: Lysine decarboxylase, inducible / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Hafnia alvei ATCC 51873 (bacteria)
Molecular weightTheoretical: 80.205281 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: MNIIAILNHM GVYFKEEPIR ELHKALEALD FQIVYPNDRE DLLKLIDNNA RLCGVIFDWD TYNLDLCEEI SAMNEHLPVY AFANTHSTL DVSLNDLRLN VEFFEYALGA AQDIAQKIRQ STDAYIDEIL PPLTKALFNY VKEGKYTFCT PGHMGGTAFQ K SPVGSIFY ...String:
MNIIAILNHM GVYFKEEPIR ELHKALEALD FQIVYPNDRE DLLKLIDNNA RLCGVIFDWD TYNLDLCEEI SAMNEHLPVY AFANTHSTL DVSLNDLRLN VEFFEYALGA AQDIAQKIRQ STDAYIDEIL PPLTKALFNY VKEGKYTFCT PGHMGGTAFQ K SPVGSIFY DFFGANAMKS DISISVGELG SLLDHSGPHK EAEEYIARTF NAERSYMVTN GTSTANKIVG MYSAPAGSTV LI DRNCHKS LTHLMMMSDI TPIYFRPTRN AYGILGGIPK SEFQHDTIAE RVAQTPNATW PVHAVVTNST YDGLLYNTDY IKE ALDVKS IHFDSAWVPY TNFSPIYKGL CGMSGGRVEG KVIYETQSTH KLLAAFSQAS MIHVKGDINE ETFNEAYMMH TSTS PHYGI VASTETAAAM MKGNAGKRLI NGSIERAIRF RKEIKRLNSE SEGWFFDVWQ PEGIDEAKCW PLDSKDNWHG FKDID NDHM YLDPIKVTLL TPGMQKDGSM ADTGIPASIV SKYLDEHGII VEKTGPYNML FLFSIGIDKT KALSLLRALT DFKRSY DLN LRVKNMLPSL YREDPEFYEN MRIQELAQGI HALIQHHNLP DLMYRAFEVL PTMVMNPHAA FQMELRGQTE EVYLEEM IG KVNANMILPY PPGVPLVMPG EMLTEESRPV LEFLQMLCEI GAHYPGFETD IHGAYRQADG RYTVKVIK

UniProtKB: Lysine decarboxylase, inducible

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Macromolecule #2: (2R)-6-amino-2-[(2E)-2-({3-hydroxy-2-methyl-5-[(phosphonooxy)meth...

MacromoleculeName: (2R)-6-amino-2-[(2E)-2-({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methylidene)hydrazin-1-yl]hexanoic acid
type: ligand / ID: 2 / Number of copies: 10 / Formula: A1BD1
Molecular weightTheoretical: 390.329 Da

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Macromolecule #3: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 2237 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab initio
Final reconstructionApplied symmetry - Point group: D5 (2x5 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 2.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.1) / Number images used: 1300000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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