Inactive and active state structures template selective tools for the human 5-HT_5A receptor

Area of Science:

• Structural biology
• Neuropharmacology
• G protein-coupled receptor research

Background:

• Serotonin receptors are crucial for cell signaling and therapeutic targets.
• The 5-hydroxytryptamine (5-HT)_5A receptor (5-HT_5AR) is the least understood among the 12 human G protein-coupled receptor members.
• A lack of selective tool compounds hinders research into 5-HT_5AR.

Purpose of the Study:

• To determine the high-resolution structures of the human 5-HT_5A receptor.
• To provide insights into the receptor's inactive and active states.
• To facilitate the development of novel, selective antagonists for 5-HT_5AR.

Main Methods:

• X-ray crystallography was used to obtain an inactive state structure of 5-HT_5AR bound to antagonist AS2674723.
• Cryo-electron microscopy (cryo-EM) was employed to determine active state structures bound to agonists lisuride, 5-carboxamidotryptamine (5-CT), and methylergometrine.
• Structure-based drug design was utilized to develop a new antagonist.

Main Results:

• Four high-resolution structures (2.73-2.80 Å) of human 5-HT_5ARs were determined.
• Structures revealed distinct inactive and active receptor conformations.
• A novel, highly selective, and potent antagonist for 5-HT_5AR was successfully developed.

Conclusions:

• The determined structures significantly advance the understanding of the 5-HT_5A receptor.
• These findings offer a structural basis for future drug discovery efforts targeting 5-HT_5AR.
• The developed antagonist serves as a valuable tool for further research.