Structure of a bacterial adhesin reveals its role in forming a mixed-species symbiotic community with diatoms on sea ice.

The calcium-induced reorientation of calcium-binding site II results in the increased exposure of several hydrophobic residues in helix IV and the linker region. While following the general mechanism of calcium modulatory proteins, whereby a hydrophobic target site is exposed, the 'calcium switch' observed in S100B appears to be unique from that of other EF-hand proteins and may provide insights into target specificity among calcium modulatory proteins.

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Bacterial cell-surface attachment of macromolecular complexes maintains the microorganism in close proximity to extracellular substrates and allows for optimal uptake of hydrolytic byproducts. The cellulosome is a large multienzyme complex used by many anaerobic bacteria for the efficient degradation of plant cell-wall polysaccharides. The mechanism of cellulosome retention to the bacterial cell surface involves a calcium-mediated protein-protein interaction between the dockerin (Doc) module from the cellulosomal scaffold and a cohesin (Coh) module of cell-surface proteins located within the proteoglycan layer. Here, we report the structure of an ultra-high-affinity (Ka ‫؍‬ 1.44 ؋ 10 10 M ؊1 ) complex between type II Doc, together with its neighboring X module from the cellulosome scaffold of Clostridium thermocellum, and a type II Coh module associated with the bacterial cell surface. Identification of X module-Doc and X module-Coh contacts reveal roles for the X module in Doc stability and enhanced Coh recognition. This extremely tight interaction involves one face of the Coh and both helices of the Doc and comprises significant hydrophobic character and a complementary extensive hydrogen-bond network. This structure represents a unique mechanism for cellsurface attachment in anaerobic bacteria and provides a rationale for discriminating between type I and type II Coh modules.cellulose degradation ͉ cellulosome ͉ protein-protein interaction ͉ calcium A naerobic bacteria rely on secreted hydrolytic enzymes for the breakdown of extracellular polysaccharides into carbon sources, which are readily taken up by the microbe and metabolized. Attachment of these enzymes to the bacterial cell surface, either as independent entities or components of multienzyme complexes, is a key mechanism for the optimal uptake of byproducts and, thus the viability of the microbe, through maintaining its close proximity to extracellular substrates and byproducts. One such complex is the cellulosome, which is responsible for the degradation of crystalline cellulose and associated plant cell-wall polysaccharides (1-6). The cellulosome from Clostridium thermocellum has been the most extensively studied of those identified to date and comprises various cellulases and hemicellulases anchored to a large, multimodular, noncatalytic scaffoldin subunit (CipA). An enzyme-associated calcium (Ca 2ϩ )-binding module termed type I Doc mediates enzyme attachment to the scaffoldin subunit through high affinity noncovalent interactions with its nine highly conserved type I cohesin (Coh) modules yet displays very little preference for particular CipA Coh modules (7,8). The balance of the scaffoldin modular architecture includes a cellulose-binding domain, an X module of unknown function, and a C-terminal type II dockerin (Doc) module. Type II Doc tethers the cellulosome to the proteoglycan layer of the bacterial cell surface through high-affinity interactions with type II Coh modules of the surface-layer homology-containing cell-surface proteins SdbA, O...

Aberrations within the PI3K/AKT signaling axis are frequently observed in numerous cancer types, highlighting the relevance of these pathways in cancer physiology and pathology. However, therapeutic interventions employing AKT inhibitors often suffer from limitations associated with target selectivity, efficacy, or dose-limiting effects. Here we present the first crystal structure of autoinhibited AKT1 in complex with the covalent-allosteric inhibitor borussertib, providing critical insights into the structural basis of AKT1 inhibition by this unique class of compounds. Comprehensive biological and preclinical evaluation of borussertib in cancer-related model systems demonstrated a strong anti-proliferative activity in cancer cell lines harboring genetic alterations within the PTEN, PI3K, and RAS signaling pathways. Furthermore, borussertib displayed antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models of mutant KRAS pancreatic and colon cancer. Significance: Borussertib, a first-in-class covalent-allosteric AKT inhibitor, displays antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models and provides a starting point for further pharmacokinetic/dynamic optimization.