Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRF₁R), a drug target in stress-related therapy, have been unsuccessful. Studies have focused on using high-resolution G protein-coupled receptor (GPCR) structures to develop drugs. X-ray free-electron lasers (XFELs), which prevent radiation damage and provide access to high-resolution compositions, have helped accelerate GPCR structural studies. We elucidated the crystal structure of CRF₁R complexed with a BMK-I-152 antagonist at 2.75 Å using fixed-target serial femtosecond crystallography. The results revealed that two unique hydrogen bonds are present in the hydrogen bond network, the stalk region forms an alpha helix and the hydrophobic network contains an antagonist binding site. We then developed two antagonists—BMK-C203 and BMK-C205—and determined the CRF₁R/BMK-C203 and CRF₁R/BMK-C205 complex structures at 2.6 and 2.2 Å, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRF₁R.

迄今为止，开发针对促肾上腺皮质激素释放激素受体 1 (CRF ₁ R) 的药物的尝试尚未成功，该受体是压力相关治疗的药物靶点。研究重点是使用高分辨率 G 蛋白偶联受体 (GPCR) 结构来开发药物。X 射线自由电子激光器 (XFEL) 可以防止辐射损伤并提供高分辨率成分，有助于加速 GPCR 结构研究。我们使用固定目标连续飞秒晶体学阐明了 CRF ₁ R 与 2.75 Å的 BMK-I-152 拮抗剂复合的晶体结构。结果表明，氢键网络中存在两个独特的氢键，茎区形成α螺旋，疏水网络包含拮抗剂结合位点。然后，我们开发了两种拮抗剂 - BMK-C203 和 BMK-C205 - 并分别确定了 2.6 和 2.2 Å 的 CRF ₁ R/BMK-C203 和 CRF _{1 R/BMK-C205 复合物结构。}BMK-C205 在小鼠中发挥显着的抗抑郁作用，因此可用于有效识别针对 CRF ₁ R的基于结构的药物。