5L2O

Crystal Structure of ALDH1A1 in complex with BUC22

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 

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This is version 1.4 of the entry. See complete history. 


Literature

Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives.

Buchman, C.D., Hurley, T.D.

(2017) J Med Chem 60: 2439-2455

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01825
  • Primary Citation of Related Structures:  
    5L13, 5L2M, 5L2N, 5L2O

  • PubMed Abstract: 

    Aldehyde dehydrogenase 2 (ALDH2), one of 19 ALDH superfamily members, catalyzes the NAD + -dependent oxidation of aldehydes to their respective carboxylic acids. In this study, we further characterized the inhibition of four psoralen and coumarin derivatives toward ALDH2 and compared them to the ALDH2 inhibitor daidzin for selectivity against five ALDH1/2 isoenzymes. Compound 2 (K i = 19 nM) binds within the aldehyde-binding site of the free enzyme species of ALDH2. Thirty-three structural analogs were examined to develop a stronger SAR profile. Seven compounds maintained or improved upon the selectivity toward one of the five ALDH1/2 isoenzymes, including compound 36, a selective inhibitor for ALDH2 (K i = 2.4 μM), and compound 32, which was 10-fold selective for ALDH1A1 (K i = 1.2 μM) versus ALDH1A2. Further medicinal chemistry on the compounds' basic scaffold could enhance the potency and selectivity for ALDH1A1 or ALDH2 and generate chemical probes to examine the unique and overlapping functions of the ALDH1/2 isoenzymes.

    • Organizational Affiliation: 

    Department of Biochemistry and Molecular Biology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Retinal dehydrogenase 1
A, B, C, D, E
A, B, C, D, E, F, G, H
501Homo sapiensMutation(s): 0 
Gene Names: ALDH1A1, ALDC, ALDH1, PUMB1
EC: 1.2.1 (PDB Primary Data), 1.2.1.36 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P00352 (Homo sapiens)
Explore P00352 
Go to UniProtKB:  P00352
PHAROS:  P00352
GTEx:  ENSG00000165092 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00352
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6ZW
Query on 6ZW
Download Ideal Coordinates CCD File 
AA [auth G]
DA [auth H]
I [auth A]
L [auth B]
O [auth C]
AA [auth G],
DA [auth H],
I [auth A],
L [auth B],
O [auth C],
Q [auth D],
T [auth E],
X [auth F]
7-(diethylamino)-4-methyl-2H-1-benzopyran-2-one
C14 H17 N O2
AFYCEAFSNDLKSX-UHFFFAOYSA-N
YB
Query on YB
Download Ideal Coordinates CCD File 
BA [auth G]
EA [auth H]
J [auth A]
M [auth B]
R [auth D]
BA [auth G],
EA [auth H],
J [auth A],
M [auth B],
R [auth D],
U [auth E],
V [auth E],
Y [auth F]
YTTERBIUM (III) ION
Yb
AWSFICBXMUKWSK-UHFFFAOYSA-N
CL
Query on CL
Download Ideal Coordinates CCD File 
CA [auth G]
FA [auth H]
K [auth A]
N [auth B]
P [auth C]
CA [auth G],
FA [auth H],
K [auth A],
N [auth B],
P [auth C],
S [auth D],
W [auth E],
Z [auth F]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
6ZW BindingDB:  5L2O Ki: min: 870, max: 1200 (nM) from 2 assay(s)
IC50: 760 (nM) from 1 assay(s)
Binding MOAD:  5L2O IC50: 760 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.984α = 80.55
b = 98.292β = 86.23
c = 127.322γ = 64.36
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-3000data reduction

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesR21 CA198409

Revision History  (Full details and data files)

  • Version 1.0: 2017-03-08
    Type: Initial release
  • Version 1.1: 2017-04-05
    Changes: Database references
  • Version 1.2: 2017-09-20
    Changes: Author supporting evidence
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references, Derived calculations, Refinement description