6B5G

ALDH1A2 liganded with NAD and (3-ethoxythiophen-2-yl){4-[4-nitro-3-(pyrrolidin-1-yl)phenyl]piperazin-1-yl}methanone (compound 6-118)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.203 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors.

Chen, Y.Zhu, J.Y.Hong, K.H.Mikles, D.C.Georg, G.I.Goldstein, A.S.Amory, J.K.Schonbrunn, E.

(2018) ACS Chem Biol 13: 582-590

  • DOI: https://doi.org/10.1021/acschembio.7b00685
  • Primary Citation of Related Structures:  
    6ALJ, 6B5G, 6B5H, 6B5I

  • PubMed Abstract: 

    Enzymes of the ALDH1A subfamily of aldehyde dehydrogenases are crucial in regulating retinoic acid (RA) signaling and have received attention as potential drug targets. ALDH1A2 is the primary RA-synthesizing enzyme in mammalian spermatogenesis and is therefore considered a viable drug target for male contraceptive development. However, only a small number of ALDH1A2 inhibitors have been reported, and information on the structure of ALDH1A2 was limited to the NAD-liganded enzyme void of substrate or inhibitors. Herein, we describe the mechanism of action of structurally unrelated reversible and irreversible inhibitors of human ALDH1A2 using direct binding studies and X-ray crystallography. All inhibitors bind to the active sites of tetrameric ALDH1A2. Compound WIN18,446 covalently reacts with the side chain of the catalytic residue Cys320, resulting in a chiral adduct in ( R) configuration. The covalent adduct directly affects the neighboring NAD molecule, which assumes a contracted conformation suboptimal for the dehydrogenase reaction. The reversible inhibitors interact predominantly through direct hydrogen bonding interactions with residues in the vicinity of Cys320 without affecting NAD. Upon interaction with inhibitors, a large flexible loop assumes regular structure, thereby shielding the active site from solvent. The precise knowledge of the binding modes provides a new framework for the rational design of novel inhibitors of ALDH1A2 with improved potency and selectivity profiles.


  • Organizational Affiliation

    Drug Discovery Department , Moffitt Cancer Center , Tampa , Florida 33612 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Retinal dehydrogenase 2
A, B, C, D
493Homo sapiensMutation(s): 0 
Gene Names: ALDH1A2RALDH2
EC: 1.2.1.36
UniProt & NIH Common Fund Data Resources
Find proteins for O94788 (Homo sapiens)
Explore O94788 
Go to UniProtKB:  O94788
PHAROS:  O94788
GTEx:  ENSG00000128918 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO94788
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
CQY Binding MOAD:  6B5G Kd: 260 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.203 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 84.6α = 90
b = 140.52β = 90
c = 164.61γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XSCALEdata scaling
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)United StatesHHSN275201300017C
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)United StatesU54HD04245

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-10
    Type: Initial release
  • Version 1.1: 2018-01-17
    Changes: Database references
  • Version 1.2: 2018-03-28
    Changes: Data collection, Database references
  • Version 1.3: 2019-12-11
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Refinement description