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- PDB-4zuk: Structure ALDH7A1 complexed with NAD+ -

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Basic information

Entry
Database: PDB / ID: 4zuk
TitleStructure ALDH7A1 complexed with NAD+
ComponentsAlpha-aminoadipic semialdehyde dehydrogenase
KeywordsOXIDOREDUCTASE / ALDEHYDE DEHYDROGENASE / NAD / LYSINE CATABOLISM
Function / homology
Function and homology information


L-aminoadipate-semialdehyde dehydrogenase activity / L-aminoadipate-semialdehyde dehydrogenase / Choline catabolism / choline catabolic process / betaine-aldehyde dehydrogenase activity / betaine-aldehyde dehydrogenase / glycine betaine biosynthetic process from choline / cellular aldehyde metabolic process / Lysine catabolism / aldehyde dehydrogenase (NAD+) ...L-aminoadipate-semialdehyde dehydrogenase activity / L-aminoadipate-semialdehyde dehydrogenase / Choline catabolism / choline catabolic process / betaine-aldehyde dehydrogenase activity / betaine-aldehyde dehydrogenase / glycine betaine biosynthetic process from choline / cellular aldehyde metabolic process / Lysine catabolism / aldehyde dehydrogenase (NAD+) / glyceraldehyde-3-phosphate dehydrogenase (NAD+) (non-phosphorylating) activity / aldehyde dehydrogenase (NAD+) activity / sensory perception of sound / mitochondrial matrix / mitochondrion / extracellular exosome / identical protein binding / nucleus / cytosol
Similarity search - Function
Aldehyde dehydrogenase family 7 member A1-like / Aldehyde Dehydrogenase; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 1 / Aldehyde Dehydrogenase; Chain A, domain 1 / Aldehyde dehydrogenases glutamic acid active site. / Aldehyde dehydrogenase, glutamic acid active site / Aldehyde dehydrogenase domain / Aldehyde dehydrogenase family / Aldehyde dehydrogenase, C-terminal ...Aldehyde dehydrogenase family 7 member A1-like / Aldehyde Dehydrogenase; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 1 / Aldehyde Dehydrogenase; Chain A, domain 1 / Aldehyde dehydrogenases glutamic acid active site. / Aldehyde dehydrogenase, glutamic acid active site / Aldehyde dehydrogenase domain / Aldehyde dehydrogenase family / Aldehyde dehydrogenase, C-terminal / Aldehyde dehydrogenase, N-terminal / Aldehyde/histidinol dehydrogenase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Alpha-aminoadipic semialdehyde dehydrogenase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.001 Å
AuthorsLuo, M. / Tanner, J.J.
CitationJournal: Biochemistry / Year: 2015
Title: Structural Basis of Substrate Recognition by Aldehyde Dehydrogenase 7A1.
Authors: Min Luo / John J Tanner /
Abstract: Aldehyde dehydrogenase 7A1 (ALDH7A1) is part of lysine catabolism and catalyzes the NAD(+)-dependent oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Herein, we describe a structural ...Aldehyde dehydrogenase 7A1 (ALDH7A1) is part of lysine catabolism and catalyzes the NAD(+)-dependent oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Herein, we describe a structural study of human ALDH7A1 focused on substrate recognition. Five crystal structures and small-angle X-ray scattering data are reported, including the first crystal structure of any ALDH7 family member complexed with α-aminoadipate. The product binds with the ε-carboxylate in the oxyanion hole, the aliphatic chain packed into an aromatic box, and the distal end of the product anchored by electrostatic interactions with five conserved residues. This binding mode resembles that of glutamate bound to the proline catabolic enzyme ALDH4A1. Analysis of ALDH7A1 and ALDH4A1 structures suggests key interactions that underlie substrate discrimination. Structures of apo ALDH7A1 reveal dramatic conformational differences from the product complex. Product binding is associated with a 16 Å movement of the C-terminus into the active site, which stabilizes the active conformation of the aldehyde substrate anchor loop. The fact that the C-terminus is part of the active site was hitherto unknown. Interestingly, the C-terminus and aldehyde anchor loop are disordered in a new tetragonal crystal form of the apoenzyme, implying that these parts of the enzyme are highly flexible. Our results suggest that the active site of ALDH7A1 is disassembled when the aldehyde site is vacant, and the C-terminus is a mobile element that forms quaternary structural interactions that aid aldehyde binding. These results are relevant to the c.1512delG genetic deletion associated with pyridoxine-dependent epilepsy, which alters the C-terminus of ALDH7A1.
History
DepositionMay 16, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 16, 2015Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Alpha-aminoadipic semialdehyde dehydrogenase
B: Alpha-aminoadipic semialdehyde dehydrogenase
C: Alpha-aminoadipic semialdehyde dehydrogenase
D: Alpha-aminoadipic semialdehyde dehydrogenase
E: Alpha-aminoadipic semialdehyde dehydrogenase
F: Alpha-aminoadipic semialdehyde dehydrogenase
G: Alpha-aminoadipic semialdehyde dehydrogenase
H: Alpha-aminoadipic semialdehyde dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)451,82424
Polymers444,9638
Non-polymers6,86116
Water24,2301345
1
A: Alpha-aminoadipic semialdehyde dehydrogenase
B: Alpha-aminoadipic semialdehyde dehydrogenase
C: Alpha-aminoadipic semialdehyde dehydrogenase
D: Alpha-aminoadipic semialdehyde dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,91212
Polymers222,4814
Non-polymers3,4318
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area21470 Å2
ΔGint-101 kcal/mol
Surface area60310 Å2
MethodPISA
2
E: Alpha-aminoadipic semialdehyde dehydrogenase
F: Alpha-aminoadipic semialdehyde dehydrogenase
G: Alpha-aminoadipic semialdehyde dehydrogenase
H: Alpha-aminoadipic semialdehyde dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,91212
Polymers222,4814
Non-polymers3,4318
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area20620 Å2
ΔGint-93 kcal/mol
Surface area60350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)155.666, 161.579, 158.932
Angle α, β, γ (deg.)90.000, 94.760, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein
Alpha-aminoadipic semialdehyde dehydrogenase / Alpha-AASA dehydrogenase / Aldehyde dehydrogenase family 7 member A1 / Antiquitin-1 / Betaine ...Alpha-AASA dehydrogenase / Aldehyde dehydrogenase family 7 member A1 / Antiquitin-1 / Betaine aldehyde dehydrogenase / Delta1-piperideine-6-carboxylate dehydrogenase / P6c dehydrogenase


Mass: 55620.367 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALDH7A1, ATQ1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P49419, L-aminoadipate-semialdehyde dehydrogenase, aldehyde dehydrogenase (NAD+), betaine-aldehyde dehydrogenase
#2: Chemical
ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#3: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Nicotinamide adenine dinucleotide


Mass: 663.425 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1345 / 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: 2.24 Å3/Da / Density % sol: 45.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Protein stock solution contained 3 mg/mL ALDH7A1 and 5 mM NAD+. The reservoir contained 0.2 M ammonium sulfate and 20% PEG 3350, 0.1 mM Bis-Tris pH 6.5.
PH range: 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1 Å
DetectorType: RDI CMOS_8M / Detector: CMOS / Date: Sep 24, 2014 / Details: Taurus-1 detector
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
111
211
ReflectionResolution: 2→62.89 Å / Num. obs: 261450 / % possible obs: 99.5 % / Redundancy: 3.8 % / Biso Wilson estimate: 24.87 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.106 / Rpim(I) all: 0.063 / Net I/σ(I): 12.7 / Num. measured all: 995590
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2-2.033.71.051.346379124720.6320.62696.1
10.96-62.893.60.02342593616430.9990.01598.6

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Processing

Software
NameVersionClassification
Aimless0.3.6data scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2J6L
Resolution: 2.001→62.89 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 23.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2183 12912 4.94 %
Rwork0.1706 248375 -
obs0.1729 261287 99.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 118.85 Å2 / Biso mean: 30.0948 Å2 / Biso min: 12.02 Å2
Refinement stepCycle: final / Resolution: 2.001→62.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms30434 0 304 1345 32083
Biso mean--42.1 29.75 -
Num. residues----4062
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00731383
X-RAY DIFFRACTIONf_angle_d1.02142653
X-RAY DIFFRACTIONf_chiral_restr0.0384802
X-RAY DIFFRACTIONf_plane_restr0.0045489
X-RAY DIFFRACTIONf_dihedral_angle_d16.19511329
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0007-2.02350.3523960.28827896829295
2.0235-2.04730.31214400.24378236867699
2.0473-2.07220.30494110.24238243865499
2.0722-2.09850.27934170.22238250866799
2.0985-2.12610.27524150.22298273868899
2.1261-2.15520.26784370.21988223866099
2.1552-2.1860.2964190.2218231865099
2.186-2.21860.28534100.21678251866199
2.2186-2.25330.27484590.20668246870599
2.2533-2.29020.28044160.2058341875799
2.2902-2.32970.25984330.19238217865099
2.3297-2.37210.24874570.19258235869299
2.3721-2.41770.26364180.193282788696100
2.4177-2.46710.25794110.189782948705100
2.4671-2.52070.23744680.184382958763100
2.5207-2.57940.23694150.175182818696100
2.5794-2.64390.24874690.174982448713100
2.6439-2.71540.2394670.181582638730100
2.7154-2.79530.25634830.18482998782100
2.7953-2.88550.22644230.179983378760100
2.8855-2.98860.22673940.177283068700100
2.9886-3.10830.24043910.182683898780100
3.1083-3.24970.24033970.180183318728100
3.2497-3.4210.19654280.168183218749100
3.421-3.63540.1924790.15382968775100
3.6354-3.9160.19643830.146383668749100
3.916-4.310.16444680.133483018769100
4.31-4.93350.14464160.115383458761100
4.9335-6.21480.16964500.142183758825100
6.2148-62.92190.16044420.13838412885499
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
10.42290.23850.07270.58350.23640.79440.0189-0.07040.049-0.0090.0777-0.1664-0.05580.1614-0.09410.16540.0120.00320.1606-0.07390.236956.889658.606934.1937
20.7775-0.31430.27160.7264-0.00430.57430.0012-0.07390.03830.07270.00050.1234-0.0171-0.0662-0.00470.1671-0.03170.0310.1871-0.06080.198322.280858.193943.3009
31.2128-0.3301-0.11690.60180.07180.43840.02020.1698-0.2889-0.0787-0.04130.06570.0924-0.08650.01960.1808-0.0106-0.01160.1521-0.04960.243745.557518.732323.6837
40.8990.1365-0.09740.6211-0.08890.47630.0416-0.2725-0.13920.1698-0.025-0.07980.0680.0582-0.01780.2089-0.0167-0.03080.22290.00440.175435.952220.355558.1062
50.82110.5333-0.10260.6198-0.16630.3574-0.06670.0966-0.0595-0.06560.05530.02910.021-0.06210.01350.1864-0.01720.01140.2527-0.11260.21223.670598.352433.1934
60.3089-0.1596-0.16450.4716-0.07330.4249-0.03490.0166-0.0310.03980.0274-0.14220.02790.00220.0050.2004-0.0411-0.00810.2264-0.09720.26158.269898.996143.4665
70.4881-0.0387-0.050.4285-0.1780.5715-0.0109-0.08050.1679-0.0311-0.01890.0404-0.1162-0.12890.03140.19930.0329-0.02020.2063-0.090.221635.6068138.020320.5648
80.8369-0.0859-0.33210.46490.14540.57820.004-0.14770.08970.08730.02-0.0024-0.0784-0.0644-0.02070.21020.0120.00520.2286-0.07120.18143.9906137.407956.5462
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1Chain AA3 - 511
2X-RAY DIFFRACTION2Chain BB3 - 511
3X-RAY DIFFRACTION3Chain CC3 - 511
4X-RAY DIFFRACTION4Chain DD3 - 511
5X-RAY DIFFRACTION5Chain EE3 - 511
6X-RAY DIFFRACTION6Chain FF3 - 511
7X-RAY DIFFRACTION7Chain GG3 - 501
8X-RAY DIFFRACTION8Chain HH3 - 511

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