The small GTPase Ras is an essential component of signal transduction pathways within the cell, controlling proliferation, differentiation, and apoptosis. Only in the GTP-bound form does Ras interact strongly with effector molecules such as Raf-kinase, thus acting as a molecular switch. In the GTP-bound form, Ras exists in a dynamic equilibrium between at least two distinct conformational states, 1(T) and 2(T), offering different functional properties of the protein. Zn2+-cyclen is a typical state 1(T) inhibitor; i.e., it interacts selectively with Ras in conformational state 1(T), a weak effector binding state. Here we report that active K-Ras4B, which is prominently found to be mutated in human tumors, exhibits a dynamic equilibrium like H-Ras, which can be modulated by Zn2+-cyclen. The titration experiments of Ras with Zn2+-cyclen indicate a cooperatively coupled binding of the ligands to the two interaction sites on Ras that could be identified for H-Ras previously. Our data further indicate that as in state 2(T) where induced fit produces the substate 2(T)* after effector binding, a corresponding substate 1(T)* can be detected at the state 1(T) mutant Ras(T35A). The interaction of Zn2+-cyclen with Ras not only shifts the equilibrium toward the weak effector binding state 1(T) but also perturbs the formation of substate 1(T)*, thus enhancing the inhibitory effect. Although Zn2+-cyclen shows an affinity for Ras in only the millimolar range, its potency of inhibition corresponds to a competitive state 2 inhibitor with micromolar binding affinity. Thus, the results demonstrate the mode of action and potency of this class of allosteric Ras inhibitors.

In this work, we experimentally investigate the allosteric transitions between conformational states on the Ras oncogene protein using high pressure crystallography. Ras protein is a small GTPase involved in central...

The Semantic Web and Linked Data concepts and technologies have empowered the scientific community with solutions to take full advantage of the increasingly available distributed and heterogeneous data in distinct silos. Additionally, FAIR Data principles established guidelines for data to be Findable, Accessible, Interoperable, and Reusable, and they are gaining traction in data stewardship. However, to explore their full potential, we must be able to transform legacy solutions smoothly into the FAIR Data ecosystem. In this paper, we introduce SCALEUS-FD, a FAIR Data extension of a legacy semantic web tool successfully used for data integration and semantic annotation and enrichment. The core functionalities of the solution follow the Semantic Web and Linked Data principles, offering a FAIR REST API for machine-to-machine operations. We applied a set of metrics to evaluate its “FAIRness” and created an application scenario in the rare diseases domain.

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Information technologies have introduced several changes in teaching and learning environments. In this scenario, the gamification technique emerges as a promising approach, considering the impact on the students' motivation and appealing to their participation. This paper describes a systematic review addressing gamification in virtual learning environments (VLE), presenting an overview on how gamification has been applied in these scenarios. This review was based on papers published in highly scored journals in the field of computers in education. The papers were selected according to the gamification theme, and the content was analyzed and a state of the art built, according to the retrieved qualitative data. The results seem to reveal that there are significant gains derived from the adoption of gamification in VLE. However, some gains are not unanimous and it depends on how the elements are applied. This paper also suggests a basis for future work aiming at applying gamification in a VLE.