Common activation mechanism of class A GPCRs.

Funder: Young Talent Program of ShanghaiClass A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature

Pressure ulcers: diagnostics and interventions aimed at wound-related complaints: a review of the literature.

Contains fulltext : 48339.pdf (publisher's version ) (Closed access)AIMS AND OBJECTIVES: To describe the current scientific evidence in the field of diagnostics and treatment of pain, malodour and exudate from pressure ulcers and to give recommendations for practice, based on these findings. BACKGROUND: Patients with pressure ulcers are confronted with symptoms of chronic wounds and impaired wound healing. Assessment and treatment of these symptoms have received very little attention. DESIGN: Systematic literature review. METHODS: Medline, CINAHL, and Cochrane, were searched for studies on pain, malodour and exudate in patients with pressure ulcers. RESULTS: The McGill Pain Questionnaire, the Visual Analogue Scale and the Faces Rating Scale are useful instruments to assess pressure ulcer related pain. Strong evidence was found to support a positive effect of (dia)morphine. Some evidence was found to support a positive effect of benzydamine gel and Eutectic Mixture of Local Anaesthetic-cream. Wound malodour is subjectively assessed. In a laboratory study, it is proved that activated charcoal is capable of absorbing gas molecules causing malodour. At present, no studies are available on the odour-absorbing capacity of activated charcoal dressings in pressure ulcer patients. Exudate is a symptom of impaired wound healing. The Pressure Sore Status Tool is a valid and reliable instrument for assessing the wound healing process. There is a possible indication that hydrocolloid positively influences healing time because the absorption of exudates is more effective. CONCLUSION: Little sound research has been performed on wound-related complaints in patients with pressure ulcers. Nevertheless several recommendations could be made on the present state of the art. RELEVANCE TO CLINICAL PRACTICE: Regarding pressure ulcer related pain, this review supports the intervention of local pain relieve in patients with pressure ulcers. Regarding pressure ulcer related odour and exudates, this study identifies the gaps in evidence and research