PDB-8t0n: Structure of Compound 4 bound to human ALDH1A1

ID or keywords:

Entry

Database: PDB / ID: 8t0n

Title

Structure of Compound 4 bound to human ALDH1A1

Components

Aldehyde dehydrogenase 1A1

Keywords

OXIDOREDUCTASE / Inhibitor Complex

Function / homology

Function and homology information

fructosamine catabolic process / 3-deoxyglucosone dehydrogenase activity / benzaldehyde dehydrogenase (NAD+) / benzaldehyde dehydrogenase (NAD+) activity / maintenance of lens transparency / gamma-aminobutyric acid biosynthetic process / retinal dehydrogenase / aminobutyraldehyde dehydrogenase / aminobutyraldehyde dehydrogenase (NAD+) activity / Fructose catabolism ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.86 Å

Authors

Hurley, T.D.

Funding support

United States, 1items

Citation

Journal: Chem.Biol.Interact. / Year: 2024
Title: Development of substituted benzimidazoles as inhibitors of human aldehyde dehydrogenase 1A isoenzymes.
Authors: Takahashi, C. / Chtcherbinine, M. / Huddle, B.C. / Wilson, M.W. / Emmel, T. / Hohlman, R.M. / McGonigal, S. / Buckanovich, R.J. / Larsen, S.D. / Hurley, T.D.

History

Deposition	Jun 1, 2023	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	May 1, 2024	Provider: repository / Type: Initial release

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	8t0n.cif.gz	299.5 KB	Display	PDBx/mmCIF format
PDB format	pdb8t0n.ent.gz	246.3 KB	Display	PDB format
PDBx/mmJSON format	8t0n.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	8t0n_validation.pdf.gz	1.1 MB	Display	wwPDB validaton report
Full document	8t0n_full_validation.pdf.gz	1.1 MB	Display
Data in XML	8t0n_validation.xml.gz	22.5 KB	Display
Data in CIF	8t0n_validation.cif.gz	32.8 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/t0/8t0n ftp://data.pdbj.org/pub/pdb/validation_reports/t0/8t0n	HTTPS FTP

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Related structure data

Related structure data	8t0tC C: citing same article (ref.)
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#13 - Jan 2001 Alcohol Dehydrogenase similarity (1) #127 - Jul 2010 Crystallins similarity (8) #89 - May 2007 Aconitase and Iron Regulatory Protein 1 similarity (8) #92 - Aug 2007 Anabolic Steroids similarity (1) #28 - Apr 2002 Anthrax Toxin similarity (1)

Deposited unit

A: Aldehyde dehydrogenase 1A1

hetero molecules

56.3 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Aldehyde dehydrogenase 1A1

hetero molecules

A: Aldehyde dehydrogenase 1A1

hetero molecules

A: Aldehyde dehydrogenase 1A1

hetero molecules

A: Aldehyde dehydrogenase 1A1

hetero molecules

defined by author
225 kDa, 4 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	109.267, 109.267, 83.168
Angle α, β, γ (deg.)	90.00, 90.00, 90.00
Int Tables number	89
Space group name H-M	P422

Components on special symmetry positions

ID	Model	Components
1	1	A-899- HOH

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Protein , 1 types, 1 molecules A

#1: Protein	Aldehyde dehydrogenase 1A1 / 3-deoxyglucosone dehydrogenase / ALDH-E1 / ALHDII / Aldehyde dehydrogenase family 1 member A1 / ...3-deoxyglucosone dehydrogenase / ALDH-E1 / ALHDII / Aldehyde dehydrogenase family 1 member A1 / Aldehyde dehydrogenase / cytosolic / Retinal dehydrogenase 1 / RALDH 1 / RalDH1 Mass: 54897.590 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ALDH1A1, ALDC, ALDH1, PUMB1 / Production host: Escherichia coli (E. coli) References: UniProt: P00352, aminobutyraldehyde dehydrogenase, benzaldehyde dehydrogenase (NAD+), aldehyde dehydrogenase (NAD+), retinal dehydrogenase

#1: Protein

Aldehyde dehydrogenase 1A1 / 3-deoxyglucosone dehydrogenase / ALDH-E1 / ALHDII / Aldehyde dehydrogenase family 1 member A1 / ...

Mass: 54897.590 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Homo sapiens (human) / Gene: ALDH1A1, ALDC, ALDH1, PUMB1 / Production host:

Escherichia coli (E. coli)
References: UniProt: P00352, aminobutyraldehyde dehydrogenase, benzaldehyde dehydrogenase (NAD+), aldehyde dehydrogenase (NAD+), retinal dehydrogenase

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Non-polymers , 5 types, 250 molecules

#2: Chemical	ChemComp-YB / YTTERBIUM (III) ION Mass: 173.040 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Yb
#3: Chemical	ChemComp-Y0B / 2-methoxy-6-{[(1-propyl-1H-benzimidazol-2-yl)amino]methyl}phenol Mass: 311.378 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₁₈H₂₁N₃O₂ / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical	ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE Mass: 663.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₁H₂₇N₇O₁₄P₂ / Comment: NAD*YM
#5: Chemical	ChemComp-CL / CHLORIDE ION Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 245 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.26 Å³/Da / Density % sol: 45.5 % / Description: Plates
Crystal grow	Temperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.4 Details: 10% PEG 3400, 200 mM NaCl, 100 mM Bis-Tris, 10 mM YbCl3 PH range: 6.2-6.6

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Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

APS

/ Beamline: 19-BM / Wavelength: 0.98 Å

Detector

Type: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 15, 2016

Radiation

Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray

Radiation wavelength

Wavelength: 0.98 Å / Relative weight: 1

Reflection

Resolution: 1.86→50 Å / Num. obs: 42689 / % possible obs: 99.5 % / Redundancy: 6.8 % / R_pim(I) all: 0.035 / R_rim(I) all: 0.094 / Χ²: 1.026 / Net I/av σ(I): 17.2 / Net I/σ(I): 12.4

Reflection shell

Diffraction-ID: 1

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Num. unique obs	CC_1/2	CC star	R_pim(I) all	R_rim(I) all	Χ²	% possible all
1.86-1.89	5.5	0.482	2036	0.865	0.963	0.219	0.531	0.881	96.7
1.89-1.93	5.9	0.4	2064	0.909	0.976	0.175	0.437	0.932	98.7
1.93-1.96	6.3	0.369	2094	0.937	0.983	0.158	0.402	1.014	99.1
1.96-2	6.6	0.32	2090	0.947	0.986	0.132	0.347	1.046	99.7
2-2.05	7.1	0.269	2115	0.967	0.992	0.106	0.289	1.093	99.7
2.05-2.09	7.2	0.241	2113	0.971	0.993	0.095	0.259	1.111	99.8
2.09-2.15	7.1	0.215	2133	0.977	0.994	0.085	0.231	1.152	99.8
2.15-2.21	7.2	0.195	2100	0.98	0.995	0.077	0.21	1.154	99.9
2.21-2.27	7.1	0.174	2115	0.981	0.995	0.069	0.187	1.116	100
2.27-2.34	7.2	0.159	2133	0.987	0.997	0.062	0.171	1.049	99.9
2.34-2.43	7.1	0.143	2110	0.988	0.997	0.057	0.154	1.019	99.9
2.43-2.52	7.1	0.137	2134	0.989	0.997	0.054	0.147	1.053	99.9
2.52-2.64	7.1	0.117	2127	0.992	0.998	0.046	0.126	0.991	99.9
2.64-2.78	7.1	0.109	2158	0.992	0.998	0.043	0.117	1.054	100
2.78-2.95	7.1	0.095	2132	0.995	0.999	0.037	0.102	0.99	99.8
2.95-3.18	7	0.082	2161	0.995	0.999	0.033	0.089	0.977	99.9
3.18-3.5	7	0.073	2170	0.995	0.999	0.029	0.079	0.957	99.9
3.5-4.01	7	0.066	2182	0.996	0.999	0.026	0.071	0.924	100
4.01-5.05	6.8	0.057	2220	0.997	0.999	0.023	0.062	1.002	99.9
5.05-50	6.2	0.057	2302	0.996	0.999	0.024	0.062	0.947	97.1

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Processing

Software

Name	Version	Classification
PHENIX	1.17.1_3660	refinement
HKL-3000		data scaling
HKL-3000		data reduction
PHENIX		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.86→36.62 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.06 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2216	1999	4.68 %	Random
R_work	0.1751	-	-	-
obs	0.1774	42676	99.43 %	-

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL

Refinement step

Cycle: LAST / Resolution: 1.86→36.62 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	3814	0	70	245	4129

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.012	4061
X-RAY DIFFRACTION	f_angle_d	1.176	5529
X-RAY DIFFRACTION	f_dihedral_angle_d	9.755	580
X-RAY DIFFRACTION	f_chiral_restr	0.062	607
X-RAY DIFFRACTION	f_plane_restr	0.008	712

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
1.86-1.91	0.3326	137	0.2473	2782	X-RAY DIFFRACTION	97
1.91-1.96	0.2506	139	0.2198	2841	X-RAY DIFFRACTION	99
1.96-2.01	0.2795	141	0.2207	2852	X-RAY DIFFRACTION	100
2.01-2.08	0.3053	141	0.2014	2882	X-RAY DIFFRACTION	100
2.08-2.15	0.2393	141	0.2021	2865	X-RAY DIFFRACTION	100
2.15-2.24	0.255	142	0.1899	2896	X-RAY DIFFRACTION	100
2.24-2.34	0.2432	143	0.1836	2888	X-RAY DIFFRACTION	100
2.34-2.47	0.2267	141	0.1811	2881	X-RAY DIFFRACTION	100
2.47-2.62	0.2398	144	0.1752	2916	X-RAY DIFFRACTION	100
2.62-2.82	0.2265	141	0.1815	2897	X-RAY DIFFRACTION	100
2.82-3.11	0.264	144	0.177	2939	X-RAY DIFFRACTION	100
3.11-3.56	0.209	145	0.1744	2945	X-RAY DIFFRACTION	100
3.56-4.48	0.18	147	0.1458	2991	X-RAY DIFFRACTION	100
4.48-36.62	0.1795	153	0.1589	3102	X-RAY DIFFRACTION	98

Refinement TLS params.

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

ID	L11 (°²)	L12 (°²)	L13 (°²)	L22 (°²)	L23 (°²)	L33 (°²)	S11 (Å °)	S12 (Å °)	S13 (Å °)	S21 (Å °)	S22 (Å °)	S23 (Å °)	S31 (Å °)	S32 (Å °)	S33 (Å °)	T11 (Å²)	T12 (Å²)	T13 (Å²)	T22 (Å²)	T23 (Å²)	T33 (Å²)	Origin x (Å)	Origin y (Å)	Origin z (Å)
1	0.5307	0.1357	-0.2612	0.3343	-0.4078	0.539	-0.2402	-0.281	-0.4503	0.195	0.0365	0.0708	0.19	-0.0073	0.0566	0.3753	0.1033	0.2465	0.255	0.1671	0.4122	54.1043	-27.8724	20.5661
2	0.809	0.1846	-0.2593	0.7048	-0.3369	0.7597	-0.1888	-0.2464	-0.1594	0.2224	0.0517	0.1024	0.048	0.0091	0.0998	0.2533	0.0754	0.0966	0.2118	0.0517	0.2047	56.4132	-14.1811	18.3851
3	0.4523	-0.3811	-0.0821	0.599	-0.1962	0.3547	-0.2197	-0.1422	-0.2076	0.187	0.1686	0.3295	0.0939	-0.1113	-0.0053	0.2752	0.0428	0.1302	0.2502	0.057	0.3658	33.3539	-10.592	18.2664
4	0.6463	0.179	-0.1448	0.4446	-0.1803	0.4696	-0.2003	-0.1696	-0.2707	0.181	0.0072	0.2025	0.2186	-0.1222	-0.122	0.3713	0.0606	0.3522	0.3738	0.1165	0.5636	23.9757	-18.2569	26.8724
5	0.7579	0.6689	-0.5952	0.5993	-0.4642	1.4953	-0.1382	-0.2569	0.0215	0.3377	0.1139	0.4547	-0.0857	-0.1662	-0.0208	0.2639	0.0934	0.1418	0.2609	0.0153	0.3654	27.4028	-2.1334	20.0444
6	0.7152	-0.1892	0.0347	0.1679	0.0672	0.1909	-0.1548	-0.0819	0.0017	0.1244	0.0836	0.0642	0.0216	-0.0061	0.0537	0.2342	0.037	0.0278	0.1867	0.0131	0.2065	54.0406	-2.3906	9.9922

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 8 through 121 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 122 through 261 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 262 through 305 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 306 through 384 )
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 385 through 454 )
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 455 through 501 )

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Protein , 1 types, 1 molecules A

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Non-polymers , 5 types, 250 molecules

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