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Structure-based drug discovery of a corticotropin-releasing hormone receptor 1 antagonist using an X-ray free-electron laser

정은지|하고은|Cho Hyun-Soo|Lee Sang Jae|Kim Hoyoung|Lim Taehyun|Lee Jee-Young|Kim Jun-Woo|Chang Nienping|Kim Si Hyun|Kim Ki Hun|Lee Jaeick|Cho Yongju|Kim Byeong Wook|Abrahamsson Alva|Kim Sung Hwan|Kim Hyo-Ji|Park Sehan|Park Jaehyun|Kim B. Moon
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2023.12|Experimental and Molecular Medicine|제55권 |pp. 2039-2050|DOI 10.1038/s12276-023-01082-1

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주제분류생화학

초록

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.

Abstract

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.

참고문헌 (55)

  1. Bortolato, A., "Structure of Class B GPCRs : new horizons for drug discovery", Br. J. Pharmacol, 171, pp.3132~3145 (2014)
  2. Hauger, R. L., "Corticotropin releasing factor(CRF)receptor signaling in the central nervous system : new molecular targets", CNS Neurol. Disord. Drug Targets, 5, pp.453~479 (2006)
  3. Behan, D. P., "Neurobiology of corticotropin releasing factor(CRF)receptors and CRF-binding protein : implications for the treatment of CNS disorders", Mol. Psychiatry, 1, pp.265~277 (1996)
  4. Cosgriff, J. P., "Cortisol hypersecretion predicts early depressive relapse after recovery with electroconvulsive therapy", Biol. Psychiatry, 28, pp.1007~1010 (1990)
  5. Mello, A. F., "Update on stress and depression : the role of the hypothalamic-pituitary-adrenal(HPA)axis", Braz. J. Psychiatry, 25, pp.231~238 (2003)
  6. Nemeroff, C. B., "The corticotropin-releasing factor (CRF) hypothesis of depression:new findings and new directions", Mol. Psychiatry, 1, pp.336~342 (1996)
  7. Nemeroff, C. B., "Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients", Science, 226, pp.1342~1344 (1984)
  8. Banki, C. M., "CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia", Am. J. Psychiatry, 144, pp.873~877 (1987)
  9. Raadsheer, F. C., "Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients", Neuroendocrinology, 60, pp.436~444 (1994)
  10. Early Release of Selected Estimates Based on Data from the 2019 National Health Interview Survey, "Clarke, T. C.", Division of Health Interview Statistics, National Center for Health Statistics, ~ (2019)
  11. Rush, A. J., "Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps : a STAR*D report", Am. J. Psychiatry, 163, pp.1905~1917 (2006)
  12. Sanders, J., "The CRF system as a therapeutic target for neuropsychiatric disorders", Trends Pharmacol. Sci, 37, pp.1045~1054 (2016)
  13. Hollenstein, K., "Structure of class B GPCR corticotropin-releasing factor receptor 1", Nature, 499, pp.438~443 (2013)
  14. Dore, A. S., "Decoding corticotropin-releasing factor receptor type 1 crystal structures", Curr. Mol. Pharmacol, 10, pp.334~344 (2017)
  15. Liang, Y. L., "Toward a structural understanding of class B GPCR peptide binding and activation", Mol. Cell, 77, pp.656~668 (2020)
  16. Ma, S., "Molecular basis for hormone recognition and activation of corticotropin-releasing factor receptors", Mol. Cell, 77, pp.669~680 (2020)
  17. Hollenstein, K., "Insights into the structure of class B GPCRs", Trends Pharmacol. Sci, 35, pp.12~22 (2014)
  18. BMK-152, a nonpeptide analogue, with high affinity and low nonspecific binding for the corticotropin-releasing factor type 1 receptor, "Synapse(New York, N. Y. )", 2011, 910~918
  19. Caffrey, M., "Crystallizing membrane proteins using lipidic mesophases", Nat. Protocols, 4, pp.706~731 (2009)
  20. Liu, W., "Preparation of microcrystals in lipidic cubic phase for serial femtosecond crystallography", Nat. Protocols, 9, pp.2123~2134 (2014)
  21. Kabsch, W., "XDS", Acta Crystallogr. D Biol. Crystallogr, 66, pp.125~132 (2010)
  22. Jaehyun Park, "Current Status of the CXI Beamline at the PAL-XFEL", Journal of the Korean Physical Society, 69(6), pp.1089~1093 (2016), 한국물리학회
  23. Kang, H. -S., "Hard X-ray free-electron laser with femtosecond-scale timing jitter", Nat. Photonics, 11, pp.708~713 (2017)
  24. Lee, D., "Nylon mesh-based sample holder for fixed-target serial femtosecond crystallography", Sci. Rep, 9, pp.6971~ (2019)
  25. Barty, A., "Cheetah : software for high-throughput reduction and analysis of serial femtosecond X-ray diffraction data", J. Appl. Crystallogr, 47, pp.1118~1131 (2014)
  26. White, T. A., "CrystFEL : a software suite for snapshot serial crystallography", J. Appl. Crystallogr, 45, pp.335~341 (2012)
  27. Battye, T. G. G., "iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM", Acta Crystallogr. Sect. D, 67, pp.271~281 (2011)
  28. Duisenberg, A., "Indexing in single-crystal diffractometry with an obstinate list of reflections", J. Appl. Crystallogr, 25, pp.92~96 (1992)
  29. Emsley, P., "Coot : model-building tools for molecular graphics", Acta Crystallogr. Sect. D, 60, pp.2126~2132 (2004)
  30. Adams, P. D., "PHENIX : a comprehensive Python-based system for macromolecular structure solution", Acta Crystallogr. Sect. D, 66, pp.213~221 (2010)
  31. Di, L., "Experimental design on single-time-point high-throughput microsomal stability assay", J. Pharm. Sci, 93, pp.1537~1544 (2004)
  32. Kim, M. J., "High-throughput screening of inhibitory potential of nine cytochrome P450 enzymes in vitro using liquid chromatography", tandem mass spectrometry, 2005, pp.19, 2651~2658
  33. Nehmé, R., "Mini-G proteins : novel tools for studying GPCRs in their active conformation", PLoS ONE, 12, pp.e0175642~ (2017)
  34. Pardridge, W. M., "Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier", J. Pharmacol. Exp. Ther, 253, pp.884~891 (1990)
  35. Chen, Y. L., "2-aryloxy-4-alkylaminopyridines : discovery of novel corticotropinreleasing factor 1 antagonists", J. Med. Chem, 51, pp.1385~1392 (2008)
  36. Webster, E. L., "In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone(CRH)receptor antagonist : suppression of pituitary ACTH release and peripheral inflammation", Endocrinology, 137, pp.5747~5750 (1996)
  37. "Integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein-coupled receptors"
  38. de Graaf, C., "Extending the structural view of class B GPCRs", Trends Biochem. Sci, 42, pp.946~960 (2017)
  39. Zhang, H., "Structure of the full-length glucagon class B G-protein-coupled receptor", Nature, 546, pp.259~264 (2017)
  40. Ehrenmann, J., "High-resolution crystal structure of parathyroid hormone 1receptor in complex with a peptide agonist", Nat. Struct. Mol. Biol, 25, pp.1086~1092 (2018)
  41. Song, G., "Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators", Nature, 546, pp.312~315 (2017)
  42. Munk, C., "An online resource for GPCR structure determination and analysis", Nat. Methods, 16, pp.151~162 (2019)
  43. Congreve, M., "Impact of GPCR structures on drug discovery", Cell, 181, pp.81~91 (2020)
  44. Wu, F., "Full-length human GLP-1 receptor structure without orthosteric ligands", Nat. Commun, 11, pp.1272~1272 (2020)
  45. Pioszak, A. A., "Molecular recognition of corticotropin-releasing factor by its G-protein-coupled receptor CRFR1", J. Biol. Chem, 283, pp.32900~32912 (2008)
  46. Meanwell, N. A, "Synopsis of some recent tactical application of bioisosteres in drug design", J. Med. Chem, 54, pp.2529~2591 (2011)
  47. Böhm, H. J., "Fluorine in medicinal chemistry", Chembiochem, 5, pp.637~643 (2004)
  48. benzimidazoles as novel class of corticotropin releasing factor 1 receptor antagonists, "Bioorg. Med. Chem", 2018, 2229~2250
  49. El-Haj, B. M., "Linking aromatic hydroxy metabolic functionalization of drug molecules to structure and pharmacologic activity", Molecules, 23, pp.2119~ (2018)
  50. David, F. V. L., "Human cytochromes P450 associated with the phase 1 metabolism of drugs and other xenobiotics: a compilation of substrates and inhibitors of the CYP1, CYP2 and CYP3 families", Curr. Med. Chem, 10, pp.1955~1972 (2003)
  51. Wong, M. L., "Chronic administration of the non-peptide CRH type 1 receptor antagonist antalarmin does not blunt hypothalamic–pituitary–adrenal axis responses to acute immobilization stress", Life Sci, 65, pp.53~58 (1999)
  52. Dalmagro, A., "Antidepressant-like effect of caffeic acid : involvement of the cellular signaling pathways", Braz. J. Pharm. Sci, 58, pp.e20023~ (2022)
  53. Jin, Z. -l, "Mouse strain differences in SSRI sensitivity correlate with serotonin transporter binding and function", Sci. Rep, 7, pp.8631~ (2017)
  54. Gu, X., "Antidepressant-like effects of auraptenol in mice", Sci. Rep, 4, pp.4433~ (2014)
  55. Ghose, A. K., "A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases", J. Comb. Chem, 1, pp.55~68 (1999)

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