Structural basis of odorant recognition by a human odorant receptor

Area of Science:

• Molecular biology
• Neuroscience
• Biochemistry

Background:

• The human sense of smell relies on approximately 400 odorant G protein-coupled receptors (GPCRs) to detect diverse odorant molecules.
• The precise mechanisms by which odorants bind to and activate these receptors are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms of odorant binding and activation in a human odorant receptor.
• To provide a high-resolution structural and mechanistic understanding of chemical recognition in the olfactory system.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structure of the active human odorant receptor OR51E2 bound to propionate.
• Site-directed mutagenesis of the odorant-binding pocket was performed.
• Molecular dynamics (MD) simulations were employed to study receptor activation.

Main Results:

• The structure revealed that propionate binds within an occluded pocket in OR51E2, with specific contacts crucial for receptor activation.
• Mutations in the odorant-binding pocket altered the receptor's selectivity for fatty acids of different chain lengths.
• MD simulations showed that propionate binding induces conformational changes in extracellular loop 3, leading to receptor activation.

Conclusions:

• Odorant selectivity is governed by tight packing interactions within the odorant-binding pocket.
• Propionate binding to OR51E2 activates the receptor through conformational changes, providing insight into vertebrate olfactory sensing.
• This study offers a high-resolution view of odorant recognition by GPCRs, advancing our understanding of the olfactory system.