Volume 28 Issue 9, September 2021

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’.

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.

The cryo-EM structure of human mitochondrial RNase P bound to precursor tRNA reveals the molecular basis for the first step of RNA processing in human mitochondria.

Human islet amyloid polypeptide (hIAPP) is a protein commonly forming aggregates in islet cells of those afflicted by type II diabetes. New structures of fibrils seeded with patient-derived material reveal a diverse repertoire of structures, some of which may resemble those appearing in vivo.

Cryo-EM structures and functional analyses of the SARS-CoV-2 B.1.1.7 variant spike protein reveal that the A570D mutation creates a molecular switch to regulate up-down conformations of the ACE2 receptor-binding domain through a pedal-bin-like mechanism.

Quantitative biochemical assays and high-resolution cryo-EM analysis reveal how the COVID-19 antiviral drug candidate molnupiravir causes lethal viral mutagenesis by the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2.

The frameshift stimulation element (FSE) of coronaviruses is an RNA structure that is required for balanced expression of viral proteins and is thus a promising drug target. A structure of the SARS-CoV-2 FSE serves as a guide for the development of antisense oligonucleotides that impair virus replication.

Cryo-EM structures of human type 1 and type 2 bradykinin receptors (B1R and B2R) reveal the basis for discrimination between the endogenous peptides des-Arg¹⁰-kallidin and bradykinin and their activation mechanism.

Two de novo designed protein classes that link phosphorylation by tyrosine and serine kinases to protein-protein association provide potential new avenues to regulating cell function.