9S3H

Crystal structure of Cryptosporidium parvum Thioredoxin Reductase in complex with Auranofin

Summary for 9S3H

• Entry DOI: 10.2210/pdb9s3h/pdb
• Descriptor: Thioredoxin reductase, FLAVIN-ADENINE DINUCLEOTIDE, GOLD ION (3 entities in total)
• Functional Keywords: reductase, flavoprotein
• Biological source: Cryptosporidium parvum
• Total number of polymer chains: 1
• Total formula weight: 57282.93

Authors

Gabriele, F.,Palerma, M.,Ardini, M.,Bogard, J.,Ippoliti, R.,Williams, D.L.,Angelucci, F. (deposition date: 2025-07-24, release date: 2026-06-03, Last modification date: 2026-06-10)

Primary citation

Gabriele, F.,Palerma, M.,Bogard, J.,Paluzzi, L.,Zineddu, S.,Geri, A.,Vitali, V.,Massai, L.,Ardini, M.,Bellelli, A.,Petukhov, P.A.,Ippoliti, R.,Messori, L.,Williams, D.L.,Angelucci, F.
Gold-containing compounds target an apicomplexan Thioredoxin reductase: Disclosing reactivity through structural and functional characterization.
Int.J.Biol.Macromol., 369:152627-152627, 2026

PubMed Abstract: Cryptosporidium spp. cause cryptosporidiosis, a severe diarrheal disease, particularly in young children and immunocompromised individuals. Treatment options are limited, and the only approved drug, nitazoxanide, is poorly effective in the most susceptible populations. Cryptosporidium relies exclusively on the thioredoxin reductase/thioredoxin (TrxR/Trx) system for redox homeostasis as Cryptosporidium lacks a glutathione reductase gene. Consistent with this vulnerability, TrxR ablation blocks parasite proliferation and sexual development, identifying TrxR as an essential drug target. C. parvum TrxR (CpTrxR) contains two redox-active cysteine motifs: a conserved N-terminal site and an apicomplexan-specific C-terminal site absent in human TrxRs. Here, by employing six structurally diverse gold-containing compounds, including clinically used agents, we probed the reactivity of CpTrxR toward these pharmacologically relevant chemotypes. Through a combination of X-ray crystallography, mass spectrometry, and functional studies, we discovered that enzyme inhibition arises from the distinct chemical properties of these compounds, which enable them to target either the N-terminal or the apicomplexan-specific C-terminal redox sites. These findings reinforce the potential of CpTrxR as a chemically tractable and parasite-selective target and establish gold-based scaffolds as a promising foundation for developing novel anti-Cryptosporidium therapeutics.

PubMed: 42162589
DOI: 10.1016/j.ijbiomac.2026.152627

Experimental method

X-RAY DIFFRACTION (3.28 Å)