Biology subjects

Masoudi, A.

Publications and source records attributed to Masoudi, A..

3 recordsLinked to original sources

bioRxiv2026

Conformational Basis of Functionally Selective Allosteric Modulation of the Angiotensin II type 1 Receptor by Small Molecules

Blockade of signaling through the angiotensin II type 1 receptor (AT1R), a prototypical G protein-coupled receptor (GPCR), by angiotensin receptor blockers (ARBs) is a major therapeutic approach to treating a wide variety of cardiovascular and renal diseases1. Like most GPCRs, the AT1R signals through two transducers, G proteins and {beta}-arrestins2,3. Previous reports have described {beta}-arrestin-biased peptide orthosteric agonists for the AT1R with potential therapeutic advantages over currently available unbiased ARBs4-6. Here we report the DNA- encoded library screening-guided isolation and pharmacological characterization of the first small molecule AT1R allosteric ligands. We use cryo-electron microscopy, double electron- electron resonance spectroscopy, molecular dynamics simulations, and targeted mutagenesis to determine their binding sites, binding modes and conformational mechanisms driving their unique and divergent modulatory effects on G protein and {beta}-arrestin pathways. Our findings uncover new mechanisms for precisely controlling the dynamic behavior of the AT1R with implications for drug development targeting this pathophysiologically important receptor family.

biochemistry↗

bioRxiv2026

Fulfilling Koch-like postulates for fungal-animal mutualists: gallery and mycangial colonization by Xyleborus ambrosia symbiotic fungi

Fungal-animal mutualisms remain significantly understudied, yet they represent some of the most successful partnerships known in nature. Fungal farming ambrosia beetles cultivate a consortium of fungal partners that include obligate filamentous members and yeasts. These fungi are maintained in highly specialized insect organs, termed mycangia, and are cultivated as food along the beetle galleries elaborated within host trees. Here, we isolated fungi from the mycangia of Xyleborus affinis ambrosia beetles using both standard ethanol-wash and ethanol-free protocols. Omitting the ethanol wash significantly increased fungal recovery and diversity. We identify two previously described filamentous species, Raffaelea arxii and R. fusca, and the yeast, Ambrosiozyma monospora, together with two new filamentous fungi, Neocosmospora affinis and Graphium ambrosium, and two novel yeasts, Alloascoidea xylebori and Wickerhamomyces ambrosius, from both gallery walls and beetle mycangia. To meet Koch-like postulates, using mycangial colonization assays, we demonstrate that all seven fungal species were individually competent at colonizing aposymbiotic X. affinis mycangia, demonstrating each as viable symbionts. Our results show that ethanol-protocols can bias recovery of mycangial fungi, leading to underestimation of fungal diversity associated with ambrosia beetles. These findings provide a framework for improved characterization of ambrosia beetle-fungal mutualisms and experimental validation of fungal symbionts.

microbiology↗

bioRxiv2024

Small Molecule Modulators of Beta-arrestins

{beta}-arrestins are multifunctional regulators of G protein-coupled receptor (GPCR) signaling, orchestrating diverse downstream signaling events and physiological responses across the vast GPCR superfamily. While GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GRKs, comparable chemical tools to study {beta}-arrestins remain lacking. Here, we report the discovery of small-molecule inhibitors that selectively target {beta}-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical, and structural analyses. These inhibitors disrupt {beta}-arrestin-engagement with agonist-activated GPCRs, impairing desensitization, internalization, and {beta}-arrestin-dependent functions while sparing G protein-receptor coupling. Cryo-EM, MD simulations, and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a cryptic pocket formed by the middle, C-, and lariat loops of {beta}-arrestin1--a critical receptor-binding interface--stabilizing a distinct conformation incompatible with GPCR engagement. Together, these findings provide a mechanistic framework for {beta}-arrestin modulation, introducing transducer-targeted strategies to fine-tune GPCR signaling and guide the development of pathway-specific therapeutics.

biochemistry↗