Biology subjects

Kvasnica, M.

Publications and source records attributed to Kvasnica, M..

3 recordsLinked to original sources

bioRxiv2025

A mechanistic framework for the recognition of chemically diverse brassinosteroids by BRI1-family receptor kinases

Brassinosteroids (BRs) are chemically diverse plant steroid hormones produced via a branched biosynthetic pathway. The potent BR brassinolide is sensed by the membrane receptor kinase BRIl and a SERK co-receptor, but the physiological functions of other abundant BRs remain to be characterized. Here, we present quantitative binding kinetics for four Arabidopsis thaliana BR receptors and fifteen BRs, which define the key chemical features required for high affinity receptor binding, ligand positioning, and co-receptor recognition. BRIl, BRLl, and BRL3 share overlapping ligand preferences, whereas BRL2 preferentially binds C28 BRs with moderate affinity. Structural analyses of BR-bound BRIl and BRL3 ectodomains, combined with extensive in vitro and in vivo mutagenesis studies reveal a high structural plasticity of the hormone binding pocket. Functional assays using structure-based BR agonists and antagonists uncover that BR receptor - co-receptor signaling complexes can recognize chemically diverse BRs, introducing an additional, intriguing layer of BR signaling regulation.

plant biology↗

bioRxiv2022

Synthesis and Biological Evaluation of New Isoxazolyl Steroids as Anti-Prostate Cancer Agents

Steroids with a nitrogen-containing heterocycle in the side chain are known as effective inhibitors of androgen signaling and/or testosterone biosynthesis, thus showing beneficial effects for the treatment of prostate cancer. In this work, a series of 3{beta}-hydroxy-5-ene steroids containing an isoxazole fragment in the side chain was synthesized. The key steps included the preparation of Weinreb amide, its conversion to acetylenic ketones, and the 1,2- or 1,4-addition of hydroxylamine, depending on the solvent used. The biological activity of the obtained compounds was studied in a number of tests, including their effects on 17-hydroxylase and 17,20-lyase activity of human CYP17A1 and the ability of selected compounds to affect the downstream androgen receptor signaling. Three derivatives diminished the transcriptional activity of androgen receptor and displayed reasonable antiproliferative activity. The candidate compound 24j, (17R)-17-((3-(2-hydroxy-propan-2-yl)isoxazol-5-yl)methyl)-androst-5-en-3{beta}-ol, suppressed the androgen receptor signaling and decreased its protein level in two prostate cancer cell lines, LNCaP and LAPC-4. Interaction of compounds with CYP17A1 and androgen receptor was confirmed and described by molecular docking.

pharmacology and toxicology↗

bioRxiv2020

Local brassinosteroid biosynthesis enables optimal root growth

Brassinosteroid hormones are indispensable for root growth and they control both cell division and cell elongation through the establishment of an increasing signaling gradient along the longitudinal root axis. Because of their limited mobility, the importance of brassinosteroid distribution for achieving the signaling maximum is largely overlooked. Expression pattern analysis of all known brassinosteroid biosynthetic enzymes revealed that not all cells in the Arabidopsis thaliana root possess full biosynthetic machinery and completion of biosynthesis relies on cell-to-cell movement of the hormone precursors. We demonstrate that brassinosteroid biosynthesis is largely restricted to the root elongation zone where it overlaps with brassinosteroid signaling maxima. Moreover, optimal root growth requires hormone concentrations, low in the meristem and high in the root elongation zone attributable to an increased biosynthesis. Our finding that spatiotemporal regulation of hormone synthesis results in a local hormone accumulation provides a paradigm for hormone-driven organ growth in the absence of long-distance hormone transport in plants.

plant biology↗