G-protein-coupled receptors (GPCRs) are important therapeutic targets and have been targeted mainly through their orthosteric site, where the endogenous agonist binds1. However, allosteric modulation has emerged as a promising and innovative strategy in the realm of GPCR drug discovery1. Here, drawing inspiration from the natural regulation of GPCRs by transmembrane proteins, we have developed GPCR exoframe modulators (GEMs), de novo designed proteins that specifically target the transmembrane domain of GPCRs. Utilizing a hallucination-like design approach, we crafted GEMs with three strategic structural prompts to achieve the desired binding modes. We selected the dopamine D1 receptor as a prototypical model and systematically investigated four GEMs. Structural studies and functional assays revealed that these GEMs bind to the transmembrane domains and function as diverse allosteric modulators, including agonist-positive allosteric modulator, negative allosteric modulator and biased allosteric modulator. The ago-PAM GEM restores the activity of various D1 receptor loss-of-function mutants, suggesting a promising therapeutic target for GPCR-related disorders. Our work introduces GEMs that target the transmembrane domain as potent agents for allosteric GPCR modulation and highlights the potential of deep learning-based approaches in the design of function-oriented membrane proteins.

The occurrence of treatment resistance in women with postpartum depression (PPD) and risk factors for treatment resistance remain less studied. This study aimed to determine the rate of treatment resistance and the associated risk factors among women with PPD in a nationwide setting. Here we conducted a nationwide register-based cohort study of 58,618 patients with a first-ever PPD during 2006-2021 in Sweden. Information on demographics, pregnancy characteristics, pre-existing physical and psychiatric conditions and treatment was retrieved from Swedish national registers. The outcome was treatment-resistant PPD (TRPPD) within 1 year following PPD diagnosis. Associations between potential risk factors and TRPPD were assessed using multivariable Poisson regression. Among the 58,618 patients with PPD, 3,522 (6.0%) met the criteria for TRPPD during 1 year after PPD diagnosis. Lower educational level, lower household income, being non-cohabiting, smoking in early pregnancy, delivery by cesarean section, pre-existing physical conditions and pre-existing psychiatric disorders were significantly associated with a higher risk of TRPPD. In addition, patients with two births (versus primiparity) or with a prior premenstrual disorder had a lower risk of TRPPD. Treatment resistance in patients with PPD is common and is notably associated with specific demographic and clinical profiles. These findings may provide grounds for practical risk assessment at PPD diagnosis and highlight the need for personalized management strategies.

Suicidality is increased among middle-aged and older autistic adults, but little is known about the underlying factors linking autism with suicidality in midlife and older age. Here we report a cross-sectional observational study of 9,979 adults (76% female) aged 50+ years who completed questionnaires measuring autistic traits, current mental health, social connections and suicidality (suicidal ideation and suicidal self-harm). We use path analysis to explore the relationship between autistic traits and suicidality and the mediating effects of current mental health, social connectedness and male/female sex. Our results find that depression, anxiety, post-traumatic stress disorder (PTSD), loneliness and social isolation all significantly mediate the relationship between autistic traits and suicidal ideation, with small effect sizes. For suicidal self-harm, male sex, depression, PTSD and social isolation were found to be mediators. We conclude that mental health difficulties and social isolation mediate higher rates of suicidality in 50+-year-olds with high autistic traits. Targeted and individually tailored interventions for people on the autism spectrum across the lifespan are important.