Study reveals how smell receptors work

Date:
August 4, 2021
Source:
Rockefeller University
Summary:
The first-ever molecular images of an olfactory receptor at work
answer decades-old questions about odor recognition.



FULL STORY ==========================================================================
All senses must reckon with the richness of the world, but nothing matches
the challenge faced by the olfactory system that underlies our sense of
smell. We need only three receptors in our eyes to sense all the colors of
the rainbow - - that's because different hues emerge as light-waves that
vary across just one dimension, their frequency. The vibrant colorful
world, however, pales in comparison to the complexity of the chemical
world, with its many millions of odors, each composed of hundreds of
molecules, all varying greatly in shape, size and properties. The smell
of coffee, for instance, emerges from a combination of more than 200
chemical components, each of which are structurally diverse, and none
of which actually smells like coffee on its own.


==========================================================================
"The olfactory system has to recognize a vast number of molecules
with only a few hundred odor receptors or even less," says Rockefeller neuroscientist Vanessa Ruta. "It's clear that it had to evolve a different
kind of logic than other sensory systems." In a new study, Ruta and her colleagues offer answers to the decades-old question of odor recognition
by providing the first-ever molecular views of an olfactory receptor
at work.

The findings, published in Nature, reveal that olfactory receptors
indeed follow a logic rarely seen in other receptors of the nervous
system. While most receptors are precisely shaped to pair with only a
few select molecules in a lock-and-key fashion, most olfactory receptors
each bind to a large number of different molecules. Their promiscuity
in pairing with a variety of odors allows each receptor to respond to
many chemical components. From there, the brain can figure out the odor
by considering the activation pattern of combinations of receptors.

Holistic recognition Olfactory receptors were discovered 30 years
ago. But scientists have not been able to actually see them up close
and decipher their structural and mechanistic workings, in part because
these receptors didn't lend themselves to commonly available molecular
imaging methods. Complicating the matter, there seems to be no rhyme or
reason to the receptors' preferences -- an individual odor receptor can
respond to compounds that are both structurally and chemically different.



==========================================================================
"To form a basic understanding of odorant recognition we need to know how
a single receptor can recognize multiple different chemicals, which is
a key feature of how the olfactory system works and has been a mystery,"
says Josefina del Ma'rmol, a postdoc in Ruta's lab.

So Ruta and del Ma'rmol, along with Mackenzie Yedlin, a research assistant
in the lab, set out to solve an odor receptor's structure taking advantage
of recent advances in cryo-electron microscopy. This technique, which
involves beaming electrons at a frozen specimen, can reveal extremely
small molecular constructs in 3D, down to their individual atoms.

The team turned to the jumping bristletail, a ground-dwelling insect whose genome has been recently sequenced and has only five kinds of olfactory receptors. Although the jumping bristletail's olfactory system is simple,
its receptors belong to a large family of receptors with tens of millions
of variants thought to exist in the hundreds of thousands of different
insect species. Despite their diversity, these receptors function the same
way: They form an ion channel -- a pore through which charged particles
flow -- that opens only when the receptor encounters its target odorant, ultimately activating the sensory cells that initiate the sense of smell.

The researchers chose OR5, a receptor from the jumping bristletail with
broad recognition ability, responding to 60 percent of small molecules
they tested.

They then examined OR5's structure alone and also bound to a chemical,
either eugenol, a common odor molecule, or DEET, the insect repellent. "We learned a lot from comparing these three structures," Ruta says. "One
of the beautiful things you can see is that in the unbound structure
the pore is closed, but in the structure where it's bound with either
eugenol or DEET, the pore has dilated and provides a pathway for ions
to flow." With the structures in hand, the team looked closer to see
exactly where and how the two chemically different molecules bind to the receptor. There have been two ideas about odor receptors' interactions
with molecules. One is that the receptors have evolved to distinguish
large swaths of molecules by responding to a partial but defining
feature of a molecule, such as a part of its shape. Other researchers
have proposed that each receptor packs multiple pockets on its surface
at once, allowing it to accommodate a number of different molecules.



==========================================================================
But what Ruta found fit neither of those scenarios. It turned out that
both DEET and eugenol bind at the same location and fit entirely inside
a simple pocket within the receptor. And surprisingly, the amino acids
lining the pocket didn't form strong, selective chemical bonds with the odorants, but only weak bonds. Whereas in most other systems, receptors
and their target molecules are good chemical matches, here they seemed
more like friendly acquaintances.

"These kinds of nonspecific chemical interactions allow different odorants
to be recognized," Ruta says. "In this way, the receptor is not selective
to a specific chemical feature. Rather, it's recognizing the more general chemical nature of the odorant," Ruta says.

And as computational modeling revealed, the same pocket could accommodate
many other odor molecules in just the same way.

But the receptor's promiscuity doesn't mean it has no specificity,
Ruta says.

Although each receptor responds to a large number of molecules, it is insensitive to others. Moreover, a simple mutation in the amino acids
of the binding site would broadly reconfigure the receptor, changing the molecules with which it prefers to bind. This latter finding also helps
to explain how insects have been able to evolve many millions of odor
receptor varieties suited for the wide range of lifestyles and habitats
they encounter.

The findings are likely representative of many olfactory receptors,
Ruta says.

"They point to key principles in odorant recognition, not only
in insects' receptors but also in receptors within our own noses
that must also detect and discriminate the rich chemical world." ========================================================================== Story Source: Materials provided by Rockefeller_University. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Josefina del Ma'rmol, Mackenzie A. Yedlin, Vanessa Ruta. The
structural
basis of odorant recognition in insect olfactory receptors. Nature,
2021; DOI: 10.1038/s41586-021-03794-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210804123451.htm

--- up 12 weeks, 5 days, 22 hours, 45 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)