Volume 18 Issue 12, December 2022

Prostate tumors, resistant to current antiandrogen therapies, represent a serious clinical challenge. A new report identifies androgen-receptor-dependent liquid condensates as being responsible in part for therapeutic resistance, but, encouragingly, also reveals a novel vulnerability amenable to drug targeting.

Clustering and multimerization of cell surface proteins (CSPs) are essential for triggering downstream intracellular signaling events. Membrane-anchored liquid–liquid phase-separation systems have now been developed to manipulate the spatiotemporal distribution and activation of CSPs.

Isoform-selective inhibition of JAK kinases is of key interest in drug discovery. A novel pocket in the JAK pseudokinase domain was targeted by an allosteric covalent inhibitor, leading to specific JAK1 inhibition and providing a deeper understanding of cytokine signaling.

This Perspective discussed selective partitioning behaviors of biomolecules and small molecules and proposed that understanding the chemical properties that control their interactions within the condensates would promote drug development.

This perspective proposes general strategies for phase-separation-related biological studies, including proper experimental designs to validate and characterize phase-separation phenomena, connections to biological functions and some caveats to avoid common misunderstandings.

This Review introduces molecular features of the phase-separating biomolecules and how they affect phase-separation behavior in a complex intracellular environment, highlighting a complex interplay between structure, sequence and environment in the phase-separation process.

Protein condensates are subcellular structures that enrich and confine molecules in cells. This Review details how condensates can be engineered with responsiveness and on-demand functions, thus pushing cellular and metabolic engineering to a new level.

Phase separation of androgen receptor underlies mutation-mediated antiandrogen resistance. A phenotypic screen enabled the discovery of ET516, which disrupts androgen receptor phase separation and effectively suppresses the growth of prostate cancer.

A membrane-tethering liquid–liquid phase-separation system was developed for programmable compartmentalization of cell-surface proteins and regulation of downstream cellular activities.

SEUSS is a transcriptional adaptor that undergoes condensation after hyperosmotic stress-induced increase of molecular crowding. The SEUSS condensates are indispensable for stress tolerance via facilitating the expression of stress-related genes.

A chemical genomics approach was used to identify regulators of drug sensitivity for pyrvinium, a cytotoxic agent with anti-cancer potential, revealing mitochondrial complex I sensitivities and a role for C1orf115 in regulating ABCB1 activity.

Metabolic labeling experiments on fermenting yeast revealed that ethanol is oxidized to acetaldehyde and acetyl-CoA and is also a major source of NADH and NADPH, demonstrating that ethanol can be consumed as a TCA cycle and redox fuel.

Chemical proteomics identified covalent ligands targeting an isoform-restricted allosteric cysteine in JAK1. The compounds inhibit JAK1-dependent signaling in immune cells with unprecedented selectivity.

A tool kit to study bacterial efflux pumps and the movement of compounds across the cell envelope was developed enabling investigation of efflux pump physiological functions, substrate specificities and profiling of efflux pump inhibitors.

Polyketides are assembled by modular polyketide synthases and undergo chemical tailoring reactions. A dehydratase domain variant catalyzes two sequential elimination reactions from thioester intermediates to produce conjugated diene modifications.

Mukherjee et al. report that AcrIF24 is an Acr-Aca fusion protein that inhibits the Csy complex and suppresses transcription from the acrIF23–acrIF24 promoter, and they present cryo-EM structures to reveal the mechanism for both roles of AcrIF24.