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- PDB-9gns: X-ray structure of Human holo aromatic L-amino acid decarboxylase... -

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Basic information

Entry
Database: PDB / ID: 9gns
TitleX-ray structure of Human holo aromatic L-amino acid decarboxylase (AADC) complex with Carbidopa at physiological pH
ComponentsAromatic-L-amino-acid decarboxylase
KeywordsBIOSYNTHETIC PROTEIN / dopa decarboxylase / DDC / aromatic L-amino acid decarboxylase / AADC / Carbidopa
Function / homology
Function and homology information


aromatic-L-amino-acid decarboxylase / catecholamine biosynthetic process / carboxylic acid metabolic process / carboxy-lyase activity / amino acid metabolic process / pyridoxal phosphate binding
Similarity search - Function
Aromatic-L-amino-acid decarboxylase / Pyridoxal-phosphate binding site / DDC / GAD / HDC / TyrDC pyridoxal-phosphate attachment site. / Pyridoxal phosphate-dependent decarboxylase / Pyridoxal-dependent decarboxylase conserved domain / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
CARBIDOPA / PYRIDOXAL-5'-PHOSPHATE / Aromatic-L-amino-acid decarboxylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.93 Å
AuthorsPerduca, M. / Bisello, G. / Bertoldi, M.
Funding support1items
OrganizationGrant numberCountry
Other private
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
DepositionSep 4, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 14, 2025Provider: repository / Type: Initial release
Revision 1.1Jun 4, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Aromatic-L-amino-acid decarboxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,6314
Polymers53,9631
Non-polymers6683
Water3,837213
1
A: Aromatic-L-amino-acid decarboxylase
hetero molecules

A: Aromatic-L-amino-acid decarboxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,2628
Polymers107,9262
Non-polymers1,3356
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_554-y,-x,-z-1/61
Buried area13400 Å2
ΔGint-67 kcal/mol
Surface area30080 Å2
Unit cell
Length a, b, c (Å)106.921, 106.921, 219.752
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Space group name HallP612(x,y,z+5/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+2/3
#8: -x,-y,z+1/2
#9: y,x,-z+1/3
#10: -y,-x,-z+5/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+1/6
Components on special symmetry positions
IDModelComponents
11A-744-

HOH

21A-772-

HOH

31A-810-

HOH

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Components

#1: Protein Aromatic-L-amino-acid decarboxylase / DOPA decarboxylase


Mass: 53963.195 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDC, hCG_1811384, tcag7.584 / Production host: Escherichia coli (E. coli)
References: UniProt: Q53Y41, aromatic-L-amino-acid decarboxylase
#2: Chemical ChemComp-PLP / PYRIDOXAL-5'-PHOSPHATE / VITAMIN B6 Phosphate


Mass: 247.142 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H10NO6P / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-142 / CARBIDOPA / KINSON / 3-(3,4-DIHYDROXY-PHENYL)-2-HYDRAZINO-2-METHYL-PROPIONIC ACID


Mass: 226.229 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H14N2O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 213 / 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: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.36 Å3/Da / Density % sol: 63.39 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.1 M Hepes, 46% PEG 200

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9198 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 25, 2023 / Details: Toroidal mirror
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9198 Å / Relative weight: 1
ReflectionResolution: 1.93→92.6 Å / Num. obs: 56043 / % possible obs: 99.4 % / Redundancy: 4.4 % / Biso Wilson estimate: 34.53 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 13.9
Reflection shellResolution: 1.93→1.98 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.509 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 3731 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
FFTphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.93→45.3 Å / SU ML: 0.1778 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 18.6689
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1924 2800 5 %
Rwork0.1743 53219 -
obs0.1752 56019 99.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 38.25 Å2
Refinement stepCycle: LAST / Resolution: 1.93→45.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3660 0 44 213 3917
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00473807
X-RAY DIFFRACTIONf_angle_d0.80895151
X-RAY DIFFRACTIONf_chiral_restr0.0485556
X-RAY DIFFRACTIONf_plane_restr0.0075657
X-RAY DIFFRACTIONf_dihedral_angle_d8.4689520
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.93-1.960.3081420.262601X-RAY DIFFRACTION99.67
1.96-20.27931190.23732642X-RAY DIFFRACTION99.53
2-2.040.23021250.20782599X-RAY DIFFRACTION97.7
2.04-2.080.22221560.18642603X-RAY DIFFRACTION99.82
2.08-2.120.19771470.17472615X-RAY DIFFRACTION99.82
2.12-2.170.19191300.17452660X-RAY DIFFRACTION99.79
2.17-2.230.19091230.17822661X-RAY DIFFRACTION99.78
2.23-2.290.21671490.1742605X-RAY DIFFRACTION99.64
2.29-2.360.2271470.18282644X-RAY DIFFRACTION99.75
2.36-2.430.21031480.1792655X-RAY DIFFRACTION99.93
2.43-2.520.20081370.17812634X-RAY DIFFRACTION99.57
2.52-2.620.20341370.1692652X-RAY DIFFRACTION99.54
2.62-2.740.20191410.17982664X-RAY DIFFRACTION99.12
2.74-2.880.18491440.18372638X-RAY DIFFRACTION98.83
2.88-3.060.20131280.19212654X-RAY DIFFRACTION98.44
3.06-3.30.19911340.19392672X-RAY DIFFRACTION99.08
3.3-3.630.20981320.18872714X-RAY DIFFRACTION99.13
3.63-4.160.16991380.15912713X-RAY DIFFRACTION98.62
4.16-5.230.17531690.14192714X-RAY DIFFRACTION98.33
5.24-45.30.1661540.16452879X-RAY DIFFRACTION96.81
Refinement TLS params.Method: refined / Origin x: 35.4979751038 Å / Origin y: -33.271031357 Å / Origin z: -9.44971325259 Å
111213212223313233
T0.277855771606 Å2-0.0215868917338 Å20.00396314544649 Å2-0.236080024472 Å20.0162137805379 Å2--0.245164622617 Å2
L0.490781599317 °2-0.035799319861 °20.0329454391827 °2-0.513712366854 °2-0.0847217880413 °2--0.470156468352 °2
S-0.0135787892708 Å °-0.0279601515447 Å °-0.0711006436191 Å °0.0934690065928 Å °0.00599879789892 Å °-0.054840756023 Å °0.0702010388558 Å °-0.0165066382249 Å °0.00864248473443 Å °
Refinement TLS groupSelection details: all

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