Biology subjects

Arvedson, T.

Publications and source records attributed to Arvedson, T..

2 recordsLinked to original sources

bioRxiv2025

An antifungal with a novel mechanism of action discovered via resistance gene-guided genome mining

Invasive fungal infections claim over two million lives annually, a problem exacerbated by rising resistance to current antifungal treatments and an increasing population of immunocompromised individuals. Despite this, antifungal drug development has stagnated, with few novel agents and fewer novel targets explored in recent decades. Here, we validate acetolactate synthase (ALS), an enzyme critical for branched-chain amino acid biosynthesis and absent in humans, as a promising target for new therapeutics. Using resistance gene-guided genome mining, we discovered a biosynthetic gene cluster in Aspergillus terreus encoding HB-35018 (1), a novel spiro-cis-decalin tetramic acid that potently inhibits ALS. Biochemical and antifungal assays demonstrate that 1 surpasses existing ALS inhibitors in efficacy against Aspergillus fumigatus and other pathogenic fungi. Structural studies via cryo-electron microscopy reveal a unique covalent binding interaction between compound 1 and ALS, distinct from known inhibitors and finally, we demonstrate that ALS is essential for the virulence in a mouse model of invasive aspergillosis. These findings position ALS as a promising target for antifungal development and demonstrate the potential of resistance gene-guided genome mining for antifungal discovery.

bioengineering↗

bioRxiv2020

Structure of human ferroportin reveals molecular basis of iron homeostasis

The serum iron level in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin negatively regulates iron absorption and recycling by inducing ferroportin internalization and degradation. Aberrant ferroportin activity can lead to diseases of iron overload, like hemochromatosis, or iron limitation anemias. Here, we determined cryogenic electron microscopy (cryo-EM) structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with cobalt, an iron mimetic, and hepcidin. These structures and accompanying molecular dynamics simulations identify two divalent metal binding sites within the N- and C-domains of ferroportin. Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway. The carboxy-terminus of hepcidin directly contacts the divalent metal in the FPN C-domain. We further show that hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. These results suggest a new model for hepcidin regulation of ferroportin, where only iron loaded ferroportin molecules are targeted for degradation. More broadly, our structural and functional insights are likely to enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis.

biochemistry↗