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A spectrum of high-risk leukemias is caused by recurrent chromosomal translocations that result in the expression of fusion proteins. In a recent article in Nature, it has been demonstrated that the oncogenic properties of one such fusion, NUP98–HOXA9, are linked to its ability to self-associate and function through aberrantly phase-separated “onco-condensates.”
After years of only low-resolution and partial assemblies, the entire human preinitiation complex (PIC), including the large and flexible Mediator and TFIID complexes, has come into focus. Five recent papers from three different research groups have transformed our understanding of transcription initiation by RNA polymerase II.
New atomic-resolution structures provide detailed insights into the molecular mechanism of telomerase, ushering in a new era of rational drug design to target telomerase in human genetic disorders and cancer.
The RNA methyltransferase METTL3 catalyzes N6-methyladenosine (m6A) modification of messenger RNAs (mRNAs). It is overexpressed in many types of cancer, including acute myelogenous leukemia (AML), and promotes cancer cell growth and tumorigenicity. Now, a selective small molecule inhibitor of METTL3 shows significant antileukemic effects in preclinical AML models, highlighting the promise of pharmacological METTL3 inhibition as a new cancer therapy.
The biogenesis of eukaryotic 20S proteasomes requires the accurate assembly of 14 closely related protein subunits and occurs in a complex series of chaperone-dependent steps. Important insights into this pathway are now provided by the high-resolution cryo-EM structures of two 20S proteasome assembly intermediates.
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.
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 Gi 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.
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.
Pervasive genome-wide transcription initiation by RNA polymerase II (Pol II) necessitates mechanisms that restrain the quantity and length of the transcripts. A new study investigates a mechanism for inducing early transcription termination, employed primarily at genomic regions producing noncoding RNAs.
The highly conserved striatin-interacting phosphatase and kinase (STRIPAK) multimeric complex regulates the Hippo signaling pathway through phosphatase activity. A recent structure of the core STRIPAK hub reveals how striatins tetramerize to serve as a scaffolding platform for the assembly of an intricate architecture, which is distinct from that of all other protein phosphatase 2A (PP2A) complexes.
Resolving RNA polymerase structures at the atomic level has revolutionized our understanding of transcription. Three articles now published in Nature Structural & Molecular Biology and Nature Communications decipher unique properties of human RNA polymerase III and propose built-in modules within the enzyme that mediate transcriptional activation, repression and antirepression.
Structures of the human serine palmitoyltransferase complex reveal the overall assembly, regulatory mechanisms and substrate selectivity of this key enzyme in sphingolipid synthesis.
The multipass transmembrane protein UNC93B1 is critical for the proper trafficking and function of many members of the Toll-like receptor (TLR) family of innate immune receptors. A new study reports two structures of UNC93B1 in complex with full-length TLR3 or TLR7 and sheds light on how this single chaperone may differentially interact with and regulate the function of individual TLRs.
NUP98 is one of the most promiscuous fusion partners involved in leukemogenic chromosomal translocations, but the myriad of partners has long obfuscated the mechanism by which these fusion proteins drive leukemia. A new mass spectrometry–based approach has produced clues that suggest an entirely new model of leukemogenesis.
