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An elegant cryo-EM and biophysical study unveils the conformational changes of the E. coli MutS mismatch repair factor. This provides a nice follow-up to the recent report from the same group characterizing how MutS scans DNA without initiating repair on correctly base-paired DNA and recruits MutL upon encountering a mismatch.
Retinal photoreceptor cyclic nucleotide-gated (CNG) ion channels convert light signals to electrical signals in the eye. Their structures have been solved at ~3 Å resolution by cryo-EM; the asymmetric subunit assembly of heteromeric CNG channels produces a unique ion-permeation pathway with an unusual gating apparatus that indicates distinct subunit contributions for ligand-dependent channel activation.
Iboxamycin (IBX) is a new oxepanoprolinamide antibiotic based on clindamycin. Crystal structures of IBX in complex with bacterial ribosomes uncover the structural mechanism of its activity against multidrug-resistant pathogens and reveal key interactions with tRNAs and 23S rRNA, including resistance-conferring rRNA methylations.
New work from Guberovic et al. sheds light on the evolution of the histone variant macroH2A1.1 and its relationship with the NAD+-using poly(ADP-ribose) polymerase PARP1. Their study shows that macroH2A1.1 has been a nuclear regulator of NAD+ flux as far back evolutionarily as pre-metazoan protists, but has been loosening the reins on PARP1, thus expanding PARP1’s cellular roles.
Transcription of eukaryotic protein-coding genes involves co-activator complexes, including TFIID and SAGA. A new study has determined the first high-resolution cryo-EM structure of the human SAGA complex, and has implications for defining SAGA function during multiple stages of eukaryotic transcription.
Structural studies of a positive allosteric modulator of the adenosine A1 receptor demonstrate the mechanisms by which stabilization of the GPCR–G protein complex bound to its endogenous agonist yields analgesic efficacy in an animal model of neuropathic pain.
The critical event in KRAS signaling and oncogenic transformation is activation of the RAF–MEK–MAPK cascade. This requires assembly of a multiprotein–lipid complex on the plasma membrane. In a tour de force of modeling, Mysore et al. now provide the first glimpse of what this structure may actually look like.
CTCF is a conserved DNA- and RNA-binding protein with roles in genome folding and transcriptional regulation. Two recent studies investigated how CTCF knockout perturbs genome biology and derails embryogenesis in zebrafish and Drosophila melanogaster, revealing contrasting effects across species.
Emerging findings provide compelling evidence that the BRCA1-binding partner BARD1 contributes yet further to BRCA1 function. BARD1 is crucial for positioning the E2 ubiquitin-conjugating enzyme that confers specificity of its ligase to residues on histone H2A, and BARD1 also promotes DNA damage–induced chromatin recruitment through an interaction with ubiquitin-conjugated Lys13 or Lys15 of H2A on the nucleosome core particle.
Molnupiravir, a wide-spectrum antiviral that is currently in phase 2/3 clinical trials for the treatment of COVID-19, is proposed to inhibit viral replication by a mechanism known as ‘lethal mutagenesis’. Two recently published studies reveal the biochemical and structural bases of how molnupiravir disrupts the fidelity of SARS-CoV-2 genome replication and prevents viral propagation by fostering error accumulation in a process referred to as ‘error catastrophe’.
The folding of ribosomal RNAs is central to the biogenesis of the mitoribosome and is a complex, stepwise process. Five recent cryo-EM studies detail the late steps of the folding and maturation of the human mitoribosomal large subunit RNA that forms the catalytic core of the ribosome: the peptidyl transferase center (PTC).
Dimeric multidomain metabotropic glutamate receptors modulate excitatory neurotransmission in the brain. Three articles in Nature provide unparalleled insights into how glutamate and drug-like molecules induce asymmetric shape changes in these multidomain receptors to promote coupling to an intracellular protein partner.
