Eukaryotic genomes are organized into distinct chromatin compartments, some of which exhibit properties of biomolecular condensates. These condensates primarily form due to chromatin-associated proteins/complexes (CAPs). CAPs play a crucial role in gene expression, functioning as either transcriptional repressors or activators. Phase separation, a well-established biophysical phenomenon, is a key driver of chromatin condensate formation by CAPs. Notably, multivalent CAPs with the ability to engage in diverse interactions promote chromatin compaction, leading to the formation of transcriptionally repressed compartments. Conversely, interactions between intrinsically disordered region (IDR)-containing transcriptional regulators, mediated by their multivalent IDRs, lead to the formation of protein-rich, transcriptionally active droplets on decondensed genomic regions. Interestingly, both repressive heterochromatin and activating euchromatin condensates exhibit spontaneous phase separation and selectively enrich components with concordant transcriptional functions. This review delves into the mechanisms by which transcriptionally repressive CAPs orchestrate the formation of repressed chromatin domains. We further explore how a diverse array of transcription-related CAPs or core histone variants, via phase separation, influence gene expression by inducing erroneous transcription events, regulating expression levels, and facilitating the interconversion of transcriptionally repressed and active regions.

The α7 nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel, plays important roles in cognition, neuroprotection, and anti-inflammation. As a potential drug target, α7 nAChR has different binding sites for different ligands, particularly agonists and positive allosteric modulators (PAMs). Ago-PAMs can both directly activate and allosterically modulate α7 nAChR. However, the mechanism underlying α7 nAChR modulation by ago-PAM has yet to be fully elucidated. Here, we present cryo-EM structures of α7 nAChR in complex with the ago-PAM GAT107 and Ca²⁺ in the open and desensitized states, respectively. Our results from both structural comparisons and functional assays suggest an allosteric mechanism underlying GAT107 modulation and calcium potentiation of α7 nAChR, involving local conformational changes in the ECD–TMD coupling region and a global structural rearrangement in the transmembrane domain. This work provides a new mechanism of α7 nAChR gating distinct from that of conventional agonist binding. These findings would aid in drug design and enrich our biophysical understanding of pentameric ligand-gated ion channels.

Nicotine is the predominant alkaloid in tobacco leaves and affects the human nervous system by interacting with nicotinic acetylcholine receptors (nAChRs). Chronic nicotine exposure leads to nAChR desensitization, while nicotine withdrawal leads to nAChR recovery. However, detailed molecular mechanisms underlying nicotine-induced nAChR desensitization and its recovery remain elusive. Here, we present cryo-EM structures of the α7 nAChR in complex with nicotine in both an open state and multiple desensitized states. Comparative analyses reveal progressive conformational changes during recovery from nicotine-induced desensitization and show that asymmetric nicotine binding disrupts the symmetry of the channel pore at the 16′ and 17′ sites. Integrating these findings with patch-clamp recordings and computational simulations, we identify an agonist-free structure that represents an atypical desensitized state closely resembling the resting conformation of α7 nAChR. These detailed mechanistic studies enhance our understanding of nicotine’s effects on α7 nAChRs.

Eukaryotic cellular organization relies on precise compartmentalization. A paradigm shift reveals that proteins with low-complexity domains (LCDs) assemble

Biomolecular condensates spatiotemporally regulate cellular biochemistry through liquid-liquid phase separation. In this Perspective, we refine the Condensate Code as a testable thermodynamic state map that integrates continuous cellular inputs, intrinsic molecular grammar and boundary conditions to govern measurable material states. Building on stickers-and-spacers and related grammar frameworks, we highlight a continuum from electrostatic coacervates to viscoelastic networks. We define active anti-grammar as an operational umbrella for localized repulsive or hydration-promoting effects that can counterbalance excessive cohesion when embedded in, modified within or recruited to dense phases. This view predicts measurable changes in partitioning, FRAP recovery, viscosity, aging and fibril-nucleation kinetics. Disruption of the code can drive pathogenic liquid-to-solid transitions and spatial uncoupling with organelle mechanotoxicity. We therefore conceptualize physical therapeutics as programmable macromolecular modulators that test whether localized anti-cohesive effects can remodel pathological material states while monitoring targeting, partitioning, oligomeric intermediates and safety.