Mechanism of cooperative strigolactone perception by the MAX2 ubiquitin ligase-receptor-substrate complex DOI Open Access
Alexandra I. Vancea, Brandon Huntington, Wieland Steinchen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

ABSTRACT Strigolactones (SLs) are a group of plant hormones that regulate various aspects growth and development. Additionally, SLs exuded into the soil promote symbiotic relationships with arbuscular mycorrhizal fungi stimulate germination parasitic plants such as Striga hermonthica . The binding hydrolysis by their receptors (D14 in Arabidopsis HTL ) ubiquitination transcriptional repressors Skp1–cullin–F-box (SCF)–type E3 ubiquitin ligases. mechanistic link between SL perception D14/HTL substrate recognition remains unclear. We identified an E3–HTL–substrate complex is sufficiently stable for cryogenic electron microscopy. This complex, composed SKP1 (ASK1) (SMAX1) from Arabidopsis, F-box (MAX2) receptor (HTL7), reveals engages bidentate association through its N D2 domains. interaction, which both conformationally compositionally dynamic, directly allosterically stabilises MAX2–(SL)HTL7 affects positioning ASK1 relative to MAX2. dynamic influences proximity domain ubiquitin-conjugated E2 enzyme. work advances our understanding how ligases translate hormone genetic adaptations.

Language: Английский

Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge DOI Creative Commons
Ruth Nussinov, Bengi Ruken Yavuz, Hyunbum Jang

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169050 - 169050

Published: Feb. 1, 2025

Language: Английский

Citations

0
A patent review of von Hippel-Lindau (vhl)-recruiting chemical matter: E3 ligase ligands for PROTACs and targeted protein degradation (2019-present) DOI Creative Commons
Aina Urbina,

Alex J. Hallatt,

Jack Robertson

et al.

Expert Opinion on Therapeutic Patents, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 42

Published: Jan. 21, 2025

The von Hippel-Lindau (VHL) E3 ubiquitin ligase has seen extensive research due to its involvement in the proteasome system and role as a tumor suppressor within hypoxia signaling pathway. VHL become an attractive target for proteolysis targeting chimeras (PROTACs), bifunctional molecules that can induce degradation of neo-substrate proteins. development inhibitors PROTACs rapid since disclosure first non-peptidic ligand (2012). Due demand more diverse sophisticated ligands be applied PROTACs, number patents disclosed risen significantly past 5 years. Herein, wide range modifications have been patented 2019 is covered. Specifically, any new or unique chemical modification established will discussed. space continues expand patent literature. There are exciting enhance physiochemical properties other alterations improve affinity itself. Further optimization no doubt lead VHL-based therapies clinical candidates.

Language: Английский

Citations

0
Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept DOI
Scott J. Hughes,

Wojciech J. Stec,

Colin Davies

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Prospective discovery of molecular glues degraders for a specific therapeutic target protein interest is an emerging strategy in drug discovery. Modification pre-existing ligands with fragments that can alter the surface lead to creation novel compounds (‘’targeted glues’’) able induce neo-interactions between and E3 ligase, resulting targeted degradation. By screening library potential BRD9 glue compounds, we have discovered potent selective, reversibly covalent degrader, AMPTX-1 . Co-immunoprecipitation-mass spectrometry experiments demonstrated cell treatment induces selective recruitment ligase DCAF16. Degradation dependent on engagement Cys58 DCAF16 formation adduct facilitated by ternary complex BRD9. degradation achieved viv o after oral dosing, demonstrating viable be drug-like, orally bioavailable promising vivo activity.

Language: Английский

Citations

0
Advancing target validation with PROTAC technology DOI
Margaret Spitz,

Aseel Kashkush,

Raphael I. Benhamou

et al.

Expert Opinion on Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: April 5, 2025

Targeted protein degradation (TPD) is a cutting-edge technology that provides new avenues for drug discovery and development. PROteolysis TArgeting Chimeras (PROTACs) are the most established advanced TPD strategy, enabling selective of disease-associated 'undruggable' proteins interest (POIs) by leveraging cell's natural machinery. To confirm PROTAC-induced proximity drives degradation, target validation ternary complex formation must be thoroughly assessed. In this perspective, authors detail some widely used in silico, structural, vitro, cellulo methods to validate PROTAC engagement formation. Additionally, they discuss growing use PROTACs as chemical probes novel identification validation. Target essential approach, ongoing studies should prioritize confirming using assays conducted under physiologically relevant cellular conditions. The believe proteomics analyses among valuable tools elucidating mechanism, selectivity, outcomes PROTACs. They also remain optimistic about future development their engagement. While rapidly advancing, it still holds vast opportunities exploration, offering significant potential further both biological research drive drugs.

Language: Английский

Citations

0
Targeted Protein Degradation: From Basic Science to Therapeutic Applications DOI
R Zhu, Xiaoyu Tang, Heng Zhang

et al.

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 18, 2025

Targeted protein degradation (TPD) is a groundbreaking approach in molecular therapeutics, enabling the selective elimination of specific proteins by leveraging cell's own machinery. In November 2024, SMART Symposium titled "Targeted Protein Degradation: from basic science to therapeutic applications" offered comprehensive communication on cutting-edge chemical strategies and emerging clinical applications this rapidly advancing field.

Language: Английский

Citations

0
Mechanism of cooperative strigolactone perception by the MAX2 ubiquitin ligase-receptor-substrate complex DOI Open Access
Alexandra I. Vancea, Brandon Huntington, Wieland Steinchen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

ABSTRACT Strigolactones (SLs) are a group of plant hormones that regulate various aspects growth and development. Additionally, SLs exuded into the soil promote symbiotic relationships with arbuscular mycorrhizal fungi stimulate germination parasitic plants such as Striga hermonthica . The binding hydrolysis by their receptors (D14 in Arabidopsis HTL ) ubiquitination transcriptional repressors Skp1–cullin–F-box (SCF)–type E3 ubiquitin ligases. mechanistic link between SL perception D14/HTL substrate recognition remains unclear. We identified an E3–HTL–substrate complex is sufficiently stable for cryogenic electron microscopy. This complex, composed SKP1 (ASK1) (SMAX1) from Arabidopsis, F-box (MAX2) receptor (HTL7), reveals engages bidentate association through its N D2 domains. interaction, which both conformationally compositionally dynamic, directly allosterically stabilises MAX2–(SL)HTL7 affects positioning ASK1 relative to MAX2. dynamic influences proximity domain ubiquitin-conjugated E2 enzyme. work advances our understanding how ligases translate hormone genetic adaptations.

Language: Английский

Citations

0