Corticotropin-releasing factor (CRF) and the three related peptides urocortins 1-3 (UCN1-UCN3) are endocrine hormones that control the stress responses by activating CRF1R and CRF2R, two members of class B G-protein-coupled receptors (GPCRs). Here, we present two cryoelectron microscopy (cryo-EM) structures of UCN1-bound CRF1R and CRF2R with the stimulatory G protein. In both structures, UCN1 adopts a single straight helix with its N terminus dipped into the receptor transmembrane bundle. Although the peptide-binding residues in CRF1R and CRF2R are different from other members of class B GPCRs, the residues involved in receptor activation and G protein coupling are conserved. In addition, both structures reveal bound cholesterol molecules to the receptor transmembrane helices. Our structures define the basis of ligand-binding specificity in the CRF receptor-hormone system, establish a common mechanism of class B GPCR activation and G protein coupling, and provide a paradigm for studying membrane protein-lipid interactions for class B GPCRs.

中文翻译：

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促肾上腺皮质激素释放因子受体的激素识别和激活的分子基础。

促肾上腺皮质激素释放因子（CRF）和三个相关肽urocortins 1-3（UCN1-UCN3）是内分泌激素，通过激活CRF1R和CRF2R（B类G蛋白偶联受体的两个成员）来控制应激反应。在这里，我们介绍了UCN1结合CRF1R和CRF2R与刺激性G蛋白的两个冷冻电子显微镜（cryo-EM）结构。在这两种结构中，UCN1均采用单个直螺旋，其N端浸入受体跨膜束中。尽管CRF1R和CRF2R中的肽结合残基不同于B类GPCR的其他成员，但保留了参与受体激活和G蛋白偶联的残基。另外，两个结构都揭示了与受体跨膜螺旋结合的胆固醇分子。