NCOA4, a dedicated autophagy receptor for mediating selective autophagy of ferritin (ferritinophagy), plays a vital role in maintaining cellular iron homeostasis. The cellular abundance of NCOA4 is regulated by the E3 ligase HERC2 that can specifically tar- get NCOA4 for proteasomal degradation under iron-- replete conditions. However, the detailed molecular mechanism governing the iron-- dependent recognition of NCOA4 by HERC2 remains elusive. Here, using multidisciplinary approaches, we systematically characterize the HERC2-- binding domain (HBD) of NCOA4 , its interaction with HERC2. We uncover that NCOA4 HBD harbors a [2Fe- 2S]- 2S] cluster and can exist in two different states, the apo- form state and the [2Fe- 2S]- 2S] cluster-bound state. Moreover, we unravel that HERC2 can effectively recognize the [2Fe- 2S]- 2S] cluster-bound NCOA4 HBD through its Cullin-- 7- PARC- HERC2- PARC- HERC2 (CPH) domain and iron-sulfur cluster-dependent NCOA4-- binding domain (INBD) with a synergistic binding mode. The determined crys- tal structures of HERC2(2540- 2700)- 2700) and its complex with the [2Fe- 2S]- 2S] cluster-bound NCOA4 HBD together with relevant biochemical and cellular results not only elucidate how NCOA4 HBD specifically senses cellular iron level by binding a [2Fe- 2S]- 2S] cluster but also reveal the molecular basis underlying the specific interaction of HERC2 with the [2Fe- 2S]- 2S] cluster-bound NCOA4 HBD. In summary, our findings provide mechanistic insights into the iron-- dependent turnover of NCOA4 by HERC2 and expand our under- standing of the regulatory mechanism of NCOA4-- mediated ferritinophagy.

The development of thermally robust olefin polymerization catalysts with high activity for high-temperature solution-phase polymerization processes represents a pivotal research domain in polymer chemistry, but it remains a challenge. In this work, we present a structurally well-defined prealkylated complex, [O-N-P]TiBn2, to catalyze high-temperature solution-phase ethylene (co)polymerization. Using modified methyl aluminoxane as an activator, the Ti complex achieved moderate ethylene/1-octene copolymerization activity (2.3 x 105 g polymer/(mol Tihatm)) at 150 degrees C with 16.4 mol % 1-octene incorporation.

Acid-sensing ion channels (ASICs), as proton-gated cation channels, play critical roles in acidosis-evoked pain signaling through their subtype-specific contributions to nociceptive pathways. ASIC1a predominantly drives central sensitization in neuropathic pain, while ASIC3 mediates peripheral inflammatory and musculoskeletal pain. While conventional analgesics, such as opioids and nonsteroidal anti-inflammatory drugs, are limited by central side effects and poor selectivity, natural toxin peptides demonstrate remarkable therapeutic potential. PcTx1 (from tarantula venom), Mambalgin (snake-derived), and APETx2 (sea anemone toxin) exhibit nanomolar affinity for ASIC extracellular domains, effectively modulating channel gating to achieve potent analgesia without addiction risks. This review systematically elucidates the molecular architecture and gating mechanisms of ASICs, providing in-depth analysis of representative toxin peptides' mechanisms towards ASICs. PcTx1 stabilizes ASIC1a in a desensitized state through acidic pocket engagement, while Mambalgin-1 locks the thumb domain in resting state to inhibit activation. APETx2 is proposed to block ASIC3 via a basic amino acid cluster binding to the site between palm and wrist domains, as suggested by homology modeling. Biosynthetic strategies have advanced significantly, with Escherichia coli serving as a cost-effective platform for rapid production of disulfide-rich peptides through engineered oxidative folding pathways (e.g., the DisCoTune system). Pichia pastoris enables secretory expression with low immunogenicity by post-translational modification systems and alpha-mating factor signal peptides. For complex modifications, mammalian cells (e.g., Chinese hamster ovary cells) provide precise folding and human-like post-translational processing. Key optimizations include solubility-enhancing tags (MBP, SUMO), affinity tags (poly-His), and chemical modifications like PEGylation to improve the pharmacokinetics of toxin peptides. Finally, the discussion extends to challenges in clinical translation of toxin peptide drugs, including incomplete ASIC subtype structural resolution and off-target effects. AI-driven design (AlphaFold2-predicted models) and stimuli-responsive nanocarriers (lipid-based systems) may address these limitations. With interdisciplinary advancements and cross-application of technologies, toxin peptides demonstrate promising potential to overcome limitations of conventional analgesic therapies.

Leucine zipper (LZ) is a unique protein structure characterized by the periodic insertion of a hydrophobic amino acid, typically leucine, every seven amino acids. In the human genome, 77 leucine zipper transcription factors (LZ TFs) with DNA-binding capabilities have been identified, including basic leucine zipper (bZIP) transcription factors and basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors. These transcription factors interact through their leucine zipper domains to form homodimers or heterodimers, constructing a complex and extensive network of transcription factor interactions and signal cascades. They exhibit diverse biological functions in various aspects such as growth and development, homeostasis maintenance, response to external stimuli, disease progression, and tumorigenesis. In this article, we will focus on the pivotal roles of leucine zipper transcription factors in cancer and summarize the small molecule inhibitors that directly target these transcription factors so far, to inform and reference the development of small molecule inhibitors of transcription factors and disease research.

The enantioselective alkylation of metal enolates serves as a particularly versatile tool for the construction of alpha-chiral carbonyls, which are ubiquitous motifs in organic chemistry. Both stoichiometric asymmetric induction reactions and catalytic asymmetric methods contribute to this field, with the latter more step-and atom-economic. In this short review, we summarize the recent achievements in this field. Both chiral lithium amide-directed manner (stoichiometric methods) and transition metal-catalyzed manner (catalytic methods) are covered separately. Moreover, both stabilized enolates and unstabilized enolates are employed as active nucleophiles, and both activated and nonactivated alkyl electrophiles serve as valid alkylati on reagents. The mechanisms, especially the origin of the stereoselectivity, and the potential applications of some representative methodologies are also included.

A direct deoxygenative alkylation of benzylic and unactivated alkyl alcohols was developed with sulfones as the alkylation reagent, the (PCN)IrHCl complex as the catalyst, and KOtBu as the additive. This protocol offers an efficient approach for the direct conversion of hydroxy groups to alkyl groups without the need for an extra hydrogen source. The utility of this reaction was demonstrated by gram-scale synthesis and derivatization of a bioactive molecule.

DNA alkylating natural products usually exhibit diverse bioactivity and serve as a crucial source of drug leads. Here, we employed genome mining guided by HTH-42 superfamily resistance gene to precisely discover a new class of DNA-alkylating antibiotics, xinghaicarcins, from Streptomyces xinghaiensis. They possess an intricate spiro-epoxide-bearing spiroketal heptacyclic scaffold fused with a pipecolic acid, assembled by a type II polyketide synthase-nonribosomal peptide synthetase hybrid system. An aminotransferase XhnB1 and a methyltransferase XhnM are identified to catalyze the formation of N-methylated pipecolic acid building block, leading to the completion of the polyketide-peptide backbone. The identification of XhnM facilitated stereochemical determination of six chiral centers in xinghaicarcins by co-crystallization. Notably, xinghaicarcins exhibit potent antibacterial activity against drug-resistant pathogens and cytotoxicity against multiple cancer cell lines. Additionally, the HTH-42 superfamily resistant protein, XhnU2, was characterized to mitigate xinghaicarcin-induced genotoxicity. This work provides comprehensive insights into structure, biosynthesis, bioactivity, and self-resistance mechanisms of xinghaicarcins, expanding diversity of DNA alkylating natural products.

Metal-catalyzed hydrogermylation of alkenes provides a direct route to organogermanium compounds that exhibit diverse applications in organic synthesis, medicinal chemistry, and materials science. The reported reactions of the type, however, have been largely restricted to activated alkenes, and those of nonactivated alkenes remain rarely known. Herein, we report Co2(CO)8-catalyzed hydrogermylation of common aryl- and alkyl-substituted terminal alkenes with HGe n Bu3 enabled by photoirradiation. The catalytic reaction delivers linear alkylgermanes in good to high yields with excellent regioselectivity. Mechanistic studies suggest a modified Chalk-Harrod mechanism for the catalytic reaction, in which photoirradiation drives the formation of coordinatively unsaturated germyl cobalt(I) intermediate.

P-stereogenic organophosphorus compounds are a class of highly important compounds due to their potentials in asymmetric catalysis both as ligands or catalysts and medicinal chemistry. Herein, we report an efficient protocol under bimetallic catalysis of Pd/Cu for highly regio-, E- and enantioselective phosphinylation of allenylic acetates with racemic secondary phosphine oxides forming a wide range of versatile P-stereogenic 1,3-dienyl phosphine oxides with 86-95% ee. The regioselectivity is unique as compared to the traditional catalytic enantioselective allenylations.

Among the regulatory factor X (RFX) transcription factor family, RFX5 is uniquely reported to bind nucleosomes and induce nucleosome remodeling in vivo. Dysfunctions in RFX5 have been implicated in various diseases. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the RFX5-nucleosome complex, revealing that the extended DNA binding domain (eDBD) of RFX5 binds to the nucleosome at superhelical location +2. RFX5 eDBD engages not only with nucleosomal DNA but also with histones through extensive interactions. Compared to the structure of a free nucleosome, RFX5 eDBD induces localized distortion of the bound DNA gyre and detachment of the adjacent DNA gyre in the RFX5-nucleosome complex. This structural alteration could potentially increase DNA accessibility and enhance transcriptional activity in vivo. Overall, our study provides novel insights into the mechanisms by which RFX5 eDBD interacts with and destabilizes nucleosomes.

The development of binuclear earth-abundant metal catalytic systems, drawing inspiration from metalloenzymes, has attracted considerable research interest in homogeneous catalysis. While current catalytic systems for alkene isomerization are mainly limited to monometallic catalysis, emerging opportunities in dinuclear catalysis present transformative potential, although their working mechanisms are still elusive. Herein, a dinuclear cobalt complex-catalyzed monoisomerization of linear alkyl alpha-olefins to 2-alkenes is disclosed, which is unusual because H2O is found to play a significant role in the control of regioselectivity, turning a mixture of multiisomers into 2-alkenes in high yields with excellent regioselectivity. DFT calculations indicated that the hydroxyl exchange step between H2O and the Co-H active intermediate acts as a functional hindrance to control the site selectivity for the selective monoisomerization.