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C16orf74/ calcimembrin (CLMB), a lipidated microprotein with roles in cancer, targets the calcineurin phosphatase to membranes. Here, authors show how CLMB uses a composite motif to form multimeric complexes with calcineurin that are required for dephosphorylation.

Fungal Pdr1p family proteins bind directly to diverse drugs and xenobiotics, resulting in activation of transcription and induction of multidrug resistance. The mechanism has analogy to regulation of multidrug resistance in vertebrates by nuclear receptors.

miRNAs are incorporated into ribonucleoprotein complexes called RNA-induced silencing complexes (RISCs) to exert RNA interference. Here the authors show that translation initiation factor eIF1A interacts with the RISCs component Ago2 to promote miR-451 biogenesis and RNA interference.

Correlating aromatic carbons attached to fluorine with meta-position hydrogens in fluorine-labelled phenylalanines can yield two-dimensional correlations with narrow linewidths in large proteins. Adapting phenylalanine-tRNA synthetase increases the incorporation rate, while expanding the genetic code enables site-specific incorporation of fluorinated phenylalanine. The resulting HC_F-transverse relaxation-optimized spectroscopy can illuminate protein dynamics and drive multiplexed drug discovery campaigns.

The structure of the apo thiolation-thioesterase di-domain fragment of the EntF non-ribosomal peptide synthetase subunit of enterobactin synthetase is solved. Extensive inter- and intra-domain motions are observed, and these are modulated by interactions with other proteins that participate in the biosynthesis of enterobactin.

NOXs are vital ROS-producing enzymes with roles in cell function and cancer. Here the authors combine computational and experimental methods to validate inhibitors for human NOX enzymes, opening avenues for redox biology-related cancer drug development.

Bloch–Siegert shifts prevent the accurate observation of resonance frequencies in NMR experiments. Here the authors present a method for homonuclear decoupling that avoids inducing Bloch–Siegert shifts and improves the sensitivity and resolution of HNCA experiments.

Sun Hur and colleagues examine the mechanism of Aire protein function underlying peripheral tissue antigen gene expression in thymic mTECs. They show that Aire condensates assemble on enhancers that are subject to intricate regulatory mechanisms, ensuring tight coordination of Aire CARD polymerization with genomic target recognition.

Lysine ubiquitination, catalysed by E3 ubiquitin ligases, is pivotal for regulating protein stability and cell signalling. Using protein semisynthesis, the roles of the C-terminal carboxylate and conformational interconversion in HECT-domain E3 catalysis are now characterized, revealing evolutionary plasticity in side chain versus backbone utilization.

Discovery of a biochemical mechanism through which lactate binds and inhibits the SUMO protease SENP1, stimulating timed degradation of cell cycle proteins, and resulting in mitotic exit.

Structures of the human METTL1–WDR4 complex are revealed, providing molecular insights into substrate recognition, modification and catalytic regulation by the N⁷-methylguanosine methyltransferase complex.

The structure and dynamics of large proteins and complexes can be studied by methyl-NMR but resonance assignment is still challenging. Here, the authors present a NMR method that leverages optimal control pulse design to unambiguously distinguish between Leu and Val using a simple 2D HMQC experiment and they apply it to several proteins including Cas9, interleukin, and human translation initiation factor eIF4a.

The development of ¹⁹F-¹³C TROSY provides a new avenue for the collection of high-sensitivity, background-free information about the structure and dynamics of challenging biomolecular systems by NMR spectroscopy.

PTEN is a key cell signaling lipid phosphatase that is regulated by C-terminal phosphorylation. Biophysical methods were used to illuminate the structural basis for PTEN regulation, which involves a dynamic N-terminal helix that influences catalysis.

VirtualFlow, an open-source drug discovery platform, enables the efficient preparation and virtual screening of ultra-large ligand libraries to identify molecules that bind with high affinity to target proteins.

Structure determination of large proteins by solution state NMR is challenging due to spectral overlap. Here the authors present a labeling strategy using 2-¹³C and 3-¹³C pyruvate as carbon source for E. coli, which increases the effective resolution of triple-resonance HNCA experiments and helps to overcome this problem.

A small molecule, inhibitor of a protein–protein interaction between the transcription factor Pdr1 and the Med15 subunit of Mediator in the fungal pathogen Candida glabrata, is identified and characterized here; the compound iKIX1 inhibits Pdr1-mediated gene activation and resensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models of disseminated and urinary tract infection.

This Perspective introduces the Minimum Information About Disorder Experiments guidelines, which provide a community consensus on the minimum information required to appropriately describe metadata on experimentally and computationally derived structural state(s) of intrinsically disordered proteins or regions.