9DY4

Crystal structure of iron-bound human ADO C18S/C239S variant soaked in hydralazine at 2.39 Angstrom resolution

This is a non-PDB format compatible entry.

Summary for 9DY4

• Entry DOI: 10.2210/pdb9dy4/pdb
• Descriptor: 2-aminoethanethiol dioxygenase, FE (II) ION, 1-hydrazinophthalazine, ... (5 entities in total)
• Functional Keywords: cysteamine dioxygenase, cobalt-bound human ado, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 30508.29

Authors

Liu, A.,Li, J. (deposition date: 2024-10-13, release date: 2025-09-24, Last modification date: 2025-10-29)

Primary citation

Shishikura, K.,Li, J.,Chen, Y.,McKnight, N.R.,Keeley, T.P.,Bustin, K.A.,Barr, E.W.,Chilkamari, S.R.,Ayub, M.,Kim, S.W.,Lin, Z.,Hu, R.M.,Hicks, K.,Wang, X.,O'Rourke, D.M.,Martin Bollinger Jr., J.,Binder, Z.A.,Parsons, W.H.,Martemyanov, K.A.,Liu, A.,Matthews, M.L.
Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma.
Sci Adv, 11:eadx7687-eadx7687, 2025

PubMed Abstract: Hydralazine (HYZ), a treatment for preeclampsia and hypertensive crisis, is listed by the World Health Organization as an essential medicine. Its mode of action has remained unknown through its seven decades of clinical use. Here, we identify 2-aminoethanethiol dioxygenase (ADO), a key mediator of targeted protein degradation, as a selective HYZ target. The drug chelates ADO's metallocofactor and can alkylate one of its ligands. The resultant inactivation stabilizes regulators of G protein signaling (RGS4 and RGS5) that ADO normally marks for proteolysis, explaining the drug's vasodilatory activity and comporting with observations of diminished RGS levels in both clinical preeclampsia and a mouse model thereof. Its inhibition of ADO suggested use of HYZ against glioblastoma (GBM); indeed, a single dose robustly senesces cultured GBM cells. By establishing ADO as a nexus for GBM and preeclampsia and connecting it to HYZ, the results create opportunities for directed tailoring of the old drug for new therapies.

PubMed: 41091880
DOI: 10.1126/sciadv.adx7687

Experimental method

X-RAY DIFFRACTION (2.39 Å)