9R6N

Crystal structure of ALDH1A2 in complex with KyA33

This is a non-PDB format compatible entry.

Summary for 9R6N

• Entry DOI: 10.2210/pdb9r6n/pdb
• Descriptor: Retinal dehydrogenase 2, 1,2-ETHANEDIOL, 3-ethyl-~{N}-(8-methyl-2-oxidanylidene-3,4-dihydro-1~{H}-quinolin-6-yl)pyridine-4-carboxamide, ... (4 entities in total)
• Functional Keywords: inhibitor, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 220544.61

Authors

Fang, C.,Esposito, M.,Huang, J.,Kang, Y. (deposition date: 2025-05-13, release date: 2025-11-19, Last modification date: 2026-01-14)

Primary citation

Fang, C.,Esposito, M.,Hars, U.,Byrne, R.T.,Song, B.,Huang, J.,Roichman, A.,Shue, L.,Cheng, X.,Proudfoot, J.,Zhao, D.,Wei, Y.,Cristea, I.M.,Rabinowitz, J.D.,Kang, Y.
Targeting autocrine retinoic acid signaling by ALDH1A2 inhibition enhances antitumor dendritic cell vaccine efficacy.
Nat.Immunol., 2026

PubMed Abstract: Strategies to stimulate dendritic cell (DC) activity, such as ex vivo generation and priming of DC vaccines, have been explored as cancer immunotherapies owing to their potential to elicit antitumor T cell responses. Despite decades of research, the success of DC vaccines has been limited, potentially because of unidentified tolerance-enforcing mechanisms. Here we show that GM-CSF-IL-4-induced differentiating DCs express ALDH1A2 and produce retinoic acid, inhibiting DC maturation. Genetic knockout of Aldh1a2 releases this natural brake and enhances DC function. We further develop an ALDH1A2 inhibitor with high potency, favorable drug-like properties and no evidence of off-target effects. Treatment with this inhibitor promotes DC activity, which in turn enhances antigen-specific T cell responses, improving the efficacy of DC vaccines. Our study demonstrates the unique role of the ALDH1A2-retinoic acid axis in regulating DC functions and further presents a new small-molecule inhibitor of ALDH1A2 as a potential immunotherapeutic agent for cancer.

PubMed: 41491403
DOI: 10.1038/s41590-025-02376-4

Experimental method

X-RAY DIFFRACTION (1.4 Å)