PDBsum entry 6b5h

Oxidoreductase/oxidoreductase inhibitor

PDB id: 6b5h

Contents

Protein chains

492 a.a.

Ligands

NAD ×4

CU4 ×4

Waters ×382

PDB id:

6b5h

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Aldh1a2 liganded with NAD and 1-(4-cyanophenyl)-n-(3-fluorophenyl)-3- [4-(methylsulfonyl)phenyl]-1h-pyrazole-4-carboxamide (compound cm121)

Structure:

Retinal dehydrogenase 2. Chain: a, b, c, d. Fragment: unp residues 26-518. Synonym: raldh2, aldehyde dehydrogenase family 1 member a2, retinaldehyde-specific dehydrogenase type 2, raldh(ii). Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: aldh1a2, raldh2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.30Å R-factor: 0.207 R-free: 0.264

Authors:

Y.Chen,J.-Y.Zhu,E.Schonbrunn

Key ref:

Y.Chen et al. (2018). Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. ACS Chem Biol, 13, 582-590. PubMed id: 29240402 DOI: 10.1021/acschembio.7b00685

Date:

29-Sep-17 Release date: 10-Jan-18

Protein chains

O94788  (AL1A2_HUMAN) -  Retinal dehydrogenase 2 from Homo sapiens

Seq: 518 a.a.

Struc: 492 a.a.

Enzyme reactions

• Enzyme class: E.C.1.2.1.36 - retinal dehydrogenase.
• Reaction: retinal + NAD⁺ + H2O = retinoate + NADH + 2 H⁺

retinal + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) + H2O = retinoate + NADH + 2 × H(+)

• Cofactor: FAD

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acschembio.7b00685

ACS Chem Biol 13:582-590 (2018)

PubMed id: 29240402

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

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

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.