RESUMEN
The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.
Asunto(s)
Proteínas de Unión al GTP Heterotriméricas/química , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Evolución Molecular , Humanos , Internet , Modelos Moleculares , Unión Proteica , Conformación Proteica , Especificidad por Sustrato , Interfaz Usuario-ComputadorRESUMEN
It is crucial to be able to forecast flows and overflows in urban drainage systems to build good and effective real-time control and warning systems. Due to computational constraints, it may often be unfeasible to employ detailed 1D hydrodynamic models for real-time purposes, and surrogate models can be used instead. In rural hydrology, forecast models are usually built or calibrated using long historical time series of, for example, flow or level observations, but such series are typically not available for the ever-changing urban drainage systems. In the current study, we therefore used a fast, reservoir-based surrogate forecast model constructed from a 1D hydrodynamic urban drainage model. Thus, we did not rely directly on historical time series data. Forecast models should preferably be able to update their internal states based on observations to ensure the best initial conditions for each forecast. We therefore used the Ensemble Kalman filter to update the surrogate model before each forecast. Water level or flow observations were assimilated into the model either directly, or indirectly using rating curves. The model forecasts were validated against observed flows and overflows. The results showed that model updating improved the forecasts up to 2â¯h ahead, but also that updating using water level observations resulted in better flow forecasts than assimilation based on flow data. Furthermore, updating with water level observations was insensitive to changes in the noise formulation used for the Ensemble Kalman filter, meaning that the method is suitable for operational settings where there is often little time and data for fine-tuning.