Volume 28 Issue 4, April 2021

AAA+ proteins (ATPases associated with various cellular activities) catalyze the energy-dependent movement or rearrangement of macromolecules. A new study addresses the important question of how to design a selective chemical inhibitor for specific proteins in this diverse superfamily. The powerful chemical genetics approach adds to a growing toolbox of applications that allow dissection of the functions of distinct AAA+ proteins in vivo, facilitating the first steps toward effective drug development.

The interaction of G protein–coupled receptors (GPCRs) with heterotrimeric G proteins plays a critical role in signal transduction processes, and multiple GPCR–G protein complexes reconstituted in detergent micelles have been visualized using cryo-EM. A new study reports the structure of neurotensin receptor 1 (NTSR1) in complex with the heterotrimeric G_i protein, assembled in a lipid environment using circularized nanodiscs. The structure sheds light on how the lipid context may influence receptor–G protein coupling and activation.

NLRP1 was the first inflammasome-forming sensor to be identified, but only recently has its mode of action been in the spotlight. Two groups now report cryo-EM structures demonstrating how NLRP1 is kept in check by the dipeptidyl peptidase DPP9, and they illuminate how DPP9 inhibition leads to NLRP1 inflammasome activation.

Inefficiently spliced first exons of enhancer-generated lncRNAs and promoter-antisense lncRNAs trigger a transcription termination checkpoint that requires WDR82, an RNA Pol II–binding protein, and its RNA-binding partner, ZC3H4.

Cryo-EM structures of the E. coli ABC transporter LolCDE in different functional states reveal mechanism of lipoprotein transport to the outer membrane of Gram-negative bacteria.

Structures of USP1−UAF complexes, including a cryo-EM structure of USP−UAF1 bound to its substrate FANCI−FANCD2, reveal molecular details of USP1−UAF1 regulation and substrate recognition.

The kinetics of prion aggregation are now dissected in mice, revealing slower PrP^Sc replication in vivo than in vitro and the contribution of aggregate fragmentation.

Cryo–EM reconstructions and atomic models reveal the mechanism of MutS–MutL DNA mismatch recognition and repair initiation.

Structural and functional analyses of RNA polymerase II−nucleosome complexes reveal how the chromatin remodeler Chd1 and the histone chaperone FACT mediate Pol II transcription through a nucleosome.

The authors describe the development of ASPIR-1, a small molecule that specifically inhibits AAA proteins by covalently modifying a cysteine residue introduced by mutagenesis at the AAA ATPase site.