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AMP-activated protein kinase (AMPK) is a principal metabolic regulator affecting growth and response to cellular stress. Comprised of catalytic and regulatory subunits, each present in multiple forms, AMPK is best described as a family of related enzymes. In recent years, AMPK has emerged as a desirable target for modulation of numerous diseases, yet clinical therapies remain elusive. Challenges result,...
The outer membrane proteins (Omps) are key factors for bacterial survival and virulence. Among the Omps that have been structurally characterized either by X-ray crystallography or by NMR in solution, the crystal structure of OmpW stands out because three of its four extracellular loops are well defined, whereas long extracellular loops in other E. coli Omps are disordered in the crystals as well...
E. coli YbgH belongs to the family of proton-dependent oligopeptide transporters (POTs), a subfamily of the major facilitator superfamily (MFS) of secondary active transporters. Like other MFS transporters, POT proteins switch between two major conformations during substrate transport. Apart from possessing a canonical 12-helix, two-domain transmembrane (TM) core, prokaryotic POT proteins usually...
SMG1, a PI3K-related kinase, plays a critical role in nonsense-mediated mRNA decay (NMD) in mammals. SMG1-mediated phosphorylation of the UPF1 helicase is an essential step during NMD initiation. Both SMG1 and UPF1 are presumably activated by UPF2, but this regulation is incompletely understood. Here we reveal that SMG1C (a complex containing SMG1, SMG8, and SMG9) contributes to regulate NMD by recruiting...
Staphylococcal protein A (SpA) is a multidomain protein consisting of five globular IgG binding domains separated by a conserved six- to nine-residue flexible linker. We collected SAXS data on the N-terminal protein-binding half of SpA (SpA-N) and constructs consisting of one to five domain modules in order to determine statistical conformation of this important S. aureus virulence factor. We fit...
The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based...
The structural understanding of eukaryotic translation lags behind that of translation on bacterial ribosomes. Here, we present two subnanometer resolution structures of S. cerevisiae 80S ribosome complexes formed with either one or two tRNAs and bound in response to an mRNA fragment containing the Kozak consensus sequence. The ribosomes adopt two globally different conformations that are related...
In this issue of Structure, Melero and colleagues use electron microscopy combined with biochemistry to provide structural insight into the complex between SMG1, SMG8, SMG9, UPF1, and UPF2, elucidating how key players in nonsense-mediated mRNA decay assemble at the initial steps of the process.
Transmembrane signaling by receptor tyrosine kinases (RTKs) entails ligand-mediated dimerization and structural rearrangement of the extracellular domains. RTK activation also depends on the specific orientation of the transmembrane domain (TMD) helices, as suggested by pathogenic, constitutively active RTK mutants. Such mutant TMDs carry polar amino acids promoting stable transmembrane helix dimerization,...
Despite tremendous successes of GPCR crystallography, the receptors with available structures represent only a small fraction of human GPCRs. An important role of the modeling community is to maximize structural insights for the remaining receptors and complexes. The community-wide GPCR Dock assessment was established to stimulate and monitor the progress in molecular modeling and ligand docking for...
Functions of many proteins are affected by posttranslational modifications of intrinsically disordered (ID) regions, yet little is known about the underlying molecular mechanisms. By combining molecular dynamics simulations and protein docking, we demonstrate that the addition of phosphates to an ID segment adjacent to the PNT domain of Ets1 directs conformational sampling toward substates that are...
Plk4 family kinases control centriole assembly. Plk4s target mother centrioles through an interaction between their cryptic polo box (CPB) and acidic regions in the centriolar receptors SPD-2/Cep192 and/or Asterless/Cep152. Here, we report a crystal structure for the CPB of C. elegans ZYG-1, which forms a Z-shaped dimer containing an intermolecular β sheet with an extended basic surface patch. Biochemical...
Members of the kinesin-13 subfamily use motor domains in an unconventional fashion to initiate microtubule (MT) depolymerization at MT ends, suggesting unique conformational transitions for lattice engagement, end adaptation, or both. Using hydrogen-deuterium exchange and electron microscopy, we explored conformational changes in free dimeric mitotic centromere-associated kinesin (MCAK) and when bound...
Polo-like kinase 4 (Plk4) is a master regulator of centriole duplication and targets to centrioles through the association of its cryptic polo box domain with centriole receptors. In this issue of Structure, Shimanovskaya and colleagues unveil a new dimeric architecture of Plk4’s cryptic polo box that reveals a conserved mechanism for centriole targeting of the kinase.
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