7LPQ

Crystal structure of Cryptococcus neoformans sterylglucosidase 1 with hit 9

Summary for 7LPQ

• Entry DOI: 10.2210/pdb7lpq/pdb
• Descriptor: Cytoplasmic protein, ~{N}-[(3~{R},5~{S})-5-(hydroxymethyl)-1-methyl-pyrrolidin-3-yl]-2-(3-oxidanylidene-4~{H}-1,4-benzoxazin-6-yl)ethanamide, GLYCEROL, ... (5 entities in total)
• Functional Keywords: glucosidase, sterylglucosidase, hydrolase
• Biological source: Cryptococcus neoformans var. grubii serotype A (strain H99 / ATCC 208821 / CBS 10515 / FGSC 9487) (Filobasidiella neoformans var. grubii); More
• Total number of polymer chains: 4
• Total formula weight: 358554.39

Authors

Pereira de Sa, N.,Del Poeta, M.,Airola, M.V. (deposition date: 2021-02-12, release date: 2021-09-01, Last modification date: 2023-10-18)

Primary citation

Pereira de Sa, N.,Taouil, A.,Kim, J.,Clement, T.,Hoffmann, R.M.,Burke, J.E.,Rizzo, R.C.,Ojima, I.,Del Poeta, M.,Airola, M.V.
Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents.
Nat Commun, 12:5885-5885, 2021

PubMed Abstract: Pathogenic fungi exhibit a heavy burden on medical care and new therapies are needed. Here, we develop the fungal specific enzyme sterylglucosidase 1 (Sgl1) as a therapeutic target. Sgl1 converts the immunomodulatory glycolipid ergosterol 3β-D-glucoside to ergosterol and glucose. Previously, we found that genetic deletion of Sgl1 in the pathogenic fungus Cryptococcus neoformans (Cn) results in ergosterol 3β-D-glucoside accumulation, renders Cn non-pathogenic, and immunizes mice against secondary infections by wild-type Cn, even in condition of CD4+ T cell deficiency. Here, we disclose two distinct chemical classes that inhibit Sgl1 function in vitro and in Cn cells. Pharmacological inhibition of Sgl1 phenocopies a growth defect of the Cn Δsgl1 mutant and prevents dissemination of wild-type Cn to the brain in a mouse model of infection. Crystal structures of Sgl1 alone and with inhibitors explain Sgl1's substrate specificity and enable the rational design of antifungal agents targeting Sgl1.

PubMed: 34620873
DOI: 10.1038/s41467-021-26163-5

Experimental method

X-RAY DIFFRACTION (2.32 Å)