Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factor

International audienc

Temperature stable solder pastes: properties and reliability

Tento článek se zabývá použitím teplotně stabilních pájecích past, což je jedním ze současných trendů v technologii pájení. Zmíněné pasty není nutné skladovat v chladničce a ani nemusejí být před použitím temperovány na pokojovou teplotu. Na současném trhu lze nalézt několik značek teplotně stabilních pájecích past. Tento článek popisuje návrh a realizaci experimentů zaměřených na ověření výrobci deklarovaných vlastností těchto past. Tyto experimenty byly zároveň navrženy a realizovány dle metodiky “Design of Experiments”. V závěru tohoto článku jsou prez entovány výsledky a doporučení pro použití těchto past v praxi.This article deals with one of the newest trends in soldering that means a using of the temperature stable solder pastes. These pas tes do not need to be stored in fridge and do not need to be tempered to the room temperature before their use. On the market, several brands of temperature stable solder pastes are available. The article describes designed and performed experiments which aim to verify the declared properties. The experiments were designed and performed according Design of Experiments methodology. The results and recommendation for practice are presented at the end of the article

New challenges in public health: syndromic surveillance as a new form of epidemiologic surveillance.

N

Mechanism of Domain Closure of Sec7 Domains and Role in BFA Sensitivity

International audienc

Structure-based discovery of an inhibitor of Arf activation by Sec7 domains through targeting of protein-protein complexes.

Small molecules that produce nonfunctional protein-protein complexes are an alternative to competitive inhibitors for the inhibition of protein functions. Here we target the activation of the small GTP-binding protein Arf1, a major regulator of membrane traffic, by the Sec7 catalytic domain of its guanine nucleotide exchange factor ARNO. The crystal structure of the Arf1-GDP/ARNO complex, which initiates the exchange reaction, was used to discover an inhibitor, LM11, using in silico screening of a flexible pocket near the Arf1/ARNO interface. Using fluorescence kinetics and anisotropy, NMR spectroscopy and mutagenesis, we show that LM11 acts following a noncompetitive mechanism in which the inhibitor targets both Arf1-GDP and the Arf1-GDP/ARNO complex and produces a nonfunctional Arf-GDP/ARNO complex whose affinity is similar to that of the native complex. In addition, LM11 recognizes features of both Arf and ARNO near the Arf/Sec7 interface, a characteristic reminiscent of the paradigm interfacial inhibitor Brefeldin A. We then show that LM11 is a cell-active inhibitor that impairs Arf-dependent trafficking structures at the Golgi. Furthermore, LM11 inhibits ARNO-dependent migration of Madin-Darby canine kidney (MDCK) cells, demonstrating that ARNO is a target of LM11 in cells. Remarkably, LM11 inhibits the activation of Arf1 but not Arf6 in vitro, pointing to a possible synergy between Arf1 and Arf6 activation by ARNO in cell migration. Our design method shows that flexible regions in protein-protein complexes provide drugable sites with the potential to develop novel tools for investigating and inhibiting signaling pathways

The science products from the SMOS CATDS: from level 2 to level 4

International audienc