6q55

Crystal structure of Cryptosporidium hominis CPSF3 in complex with Compound 61

spinqualitylabelsall models 6q55, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6q55 is a 1 chain structure with sequence from Cryht. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, HJB, IPA, MG, ZN Gene: CHUDEA8_460 (CRYHT) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Cryptosporidium is an intestinal pathogen that causes severe but self-limiting diarrhea in healthy humans, yet it can turn into a life-threatening, unrelenting infection in immunocompromised patients and young children. Severe diarrhea is recognized as the leading cause of mortality for children below 5 years of age in developing countries. The only approved treatment against cryptosporidiosis, nitazoxanide, has limited efficacy in the most vulnerable patient populations, including malnourished children, and is ineffective in immunocompromised individuals. Here, we investigate inhibition of the parasitic cleavage and polyadenylation specificity factor 3 (CPSF3) as a strategy to control Cryptosporidium infection. We show that the oxaborole AN3661 selectively blocked Cryptosporidium growth in human HCT-8 cells, and oral treatment with AN3661 reduced intestinal parasite burden in both immunocompromised and neonatal mouse models of infection with greater efficacy than nitazoxanide. Furthermore, we present crystal structures of recombinantly produced Cryptosporidium CPSF3, revealing a mechanism of action whereby the mRNA processing activity of this enzyme is efficiently blocked by the binding of the oxaborole group at the metal-dependent catalytic center. Our data provide insights that may help accelerate the development of next-generation anti-Cryptosporidium therapeutics. Metal-captured inhibition of pre-mRNA processing activity by CPSF3 controls Cryptosporidium infection.,Swale C, Bougdour A, Gnahoui-David A, Tottey J, Georgeault S, Laurent F, Palencia A, Hakimi MA Sci Transl Med. 2019 Nov 6;11(517). pii: 11/517/eaax7161. doi:, 10.1126/scitranslmed.aax7161. PMID:31694928 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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