Activation of the A2A adenosine G-protein-coupled receptor by conformational selection.

Conformational selection and induced fit are two prevailing mechanisms to explain the molecular basis for ligand-based activation of receptors. G-protein-coupled receptors are the largest class of cell surface receptors and are important drug targets. A molecular understanding of their activation mechanism is critical for drug discovery and design. However, direct evidence that addresses how agonist binding leads to the formation of an active receptor state is scarce. Here we use (19)F nuclear magnetic resonance to quantify the conformational landscape occupied by the adenosine A2A receptor (A2AR), a prototypical class A G-protein-coupled receptor. We find an ensemble of four states in equilibrium: (1) two inactive states in millisecond exchange, consistent with a formed (state S1) and a broken (state S2) salt bridge (known as 'ionic lock') between transmembrane helices 3 and 6; and (2) two active states, S3 and S3', as identified by binding of a G-protein-derived peptide. In contrast to a recent study of the ß2-adrenergic receptor, the present approach allowed identification of a second active state for A2AR. Addition of inverse agonist (ZM241385) increases the population of the inactive states, while full agonists (UK432097 or NECA) stabilize the active state, S3', in a manner consistent with conformational selection. In contrast, partial agonist (LUF5834) and an allosteric modulator (HMA) exclusively increase the population of the S3 state. Thus, partial agonism is achieved here by conformational selection of a distinct active state which we predict will have compromised coupling to the G protein. Direct observation of the conformational equilibria of ligand-dependent G-protein-coupled receptor and deduction of the underlying mechanisms of receptor activation will have wide-reaching implications for our understanding of the function of G-protein-coupled receptor in health and disease.

Gestão de desempenho por competências: integrando a gestão por competências, o balanced scorecard e a avaliação 360 graus / Competence-based performance assessment: a model which integrates competence-based management, balanced scorecard and 360º feedback

Este artigo avalia a percepção de funcionários do Banco do Brasil acerca do novo modelo de gestão de desempenho adotado pela empresa. A pesquisa, de caráter descritivo e exploratório, utilizou-se de questionário semi-estruturado para coleta de dados quantitativos e qualitativos. A amostra foi constituída por 532 funcionários de nove unidades do banco, nas quais o modelo foi implementado para fins de validação. Foram realizadas análises descritivas, de variância e fatorial entre as variáveis componentes do estudo, e análise de conteúdo dos dados qualitativos. Os resultados indicam ser muito positiva a percepção dos sujeitos da pesquisa. O novo instrumento foi considerado mais eficaz, democrático e participativo, conseguindo integrar pressupostos de modelos e instrumentos de gestão referenciados pela literatura como modernos e eficazes, como a gestão por competências, o balanced scorecard e a avaliação 360 graus. Para finalizar, são apresentadas recomendações práticas e sugestões para realização de pesquisas futuras.

The present work aims to assess the perception of Bank of Brazil employees on the new model of performance assessment adopted by the bank. This exploratory and descriptive research used a semi-structured questionnaire to collect the quantitative and qualitative data. The sample consisted of 532 employees working in the nine branches of the bank where the model was implemented for validation. Descriptive, factorial and variance analyses were made on the variables involved in the study, and analysis of the qualitative data. The new tool was considered more effective, democratic, participative and able to integrate postulates of management models and tools such as Competence-Based Management, Balanced Scorecard and 360º Feedback, which are accredited by the literature as being modern and effective. Practical advice and future directions for this sort of research are provided.