Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.
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Article Synopsis
- Peripuberty is a crucial time for brain development, and blocking CRFR1 receptors in young rats helps minimize negative effects of early-life stress on neural function and behavior.
- In an experiment, male rats showed immediate behavioral changes like reduced prepulse inhibition (PPI) after receiving a CRFR1 antagonist, while females only exhibited differences in behavior after becoming adults.
- Long-term gene expression changes in the amygdala indicate that the effects of CRFR1 blockage during peripuberty impact different neural pathways in males and females, emphasizing the importance of understanding these effects for adolescent mental health.
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