Shedding light on receptor selectivity: “one of the most comprehensive projects in my entire scientific career”
Researchers have shown how receptors selectively recognize chemical messengers, insights that could guide protein engineering and drug design going forward.
Different receptors respond to different neurotransmitters or hormones, such as adrenaline involved in the fight-or-flight response, or dopamine linked to reward and motivation. Both the receptors themselves and the substances they recognize are often very similar, but still makes the body react in completely different ways.
How the receptors know whether to respond to adrenaline or dopamine with such high precision has puzzled researchers from SciLifeLab and Uppsala University. To solve this mystery, they studied the receptors at the molecular level and began swapping out small parts of the receptors’ building blocks. Step by step, they tested how much is actually required to change the receptor’s preference.
“This is one of the most comprehensive projects in my entire scientific career,” says Dan Larhammar, SciLifeLab Group Leader and Uppsala University researcher.
Shedding light on selectivity
G protein-coupled receptors (GPCRs) are central regulators of physiological processes and therefore major targets in drug discovery. The researchers set out to shed light on the structural mechanisms of GPCR selectivity.
“It turned out that surprisingly few changes were needed — and in places one wouldn’t have initially expected”
They identified amino acids responsible for ligand selectivity in two closely related groups of receptors, the β-adrenergic and D1-like dopamine receptors. By modifying these amino acids, they made each receptor prefer the other’s native ligand. Importantly, and unexpected to the researchers, this selectivity is governed not only by residues interacting with the ligand, but also by regions outside of the primary binding site.
“It turned out that surprisingly few changes were needed — and in places one wouldn’t have initially expected,” says Jens Carlsson, SciLifeLab Fellow alumni and Uppsala University researcher, who coordinated the project across international partners, Karolinska Institutet, and three SciLifeLab teams: the groups of Carlsson and Larhammar, as well as Lucie Delemotte.
To uncover the molecular mechanisms, the researchers used a combination of experimental and computational approaches, including pharmacological assays, cryo-electron microscopy, bioinformatics and simulations.
“My big eureka moment was when I realized that evolution probably took different paths if a receptor evolved from dopamine-preferring to noradrenaline-preferring, rather than if it evolved in the opposite direction. A moment of great satisfaction was when our studies of additional receptor subtypes for dopamine and noradrenaline confirmed our initial results,” says Dan Larhammar.
An easily accessible server to study ligand selectivity in GPCRs is provided, to enable other scientists to take these findings further.
Designing new receptors
The researchers now believe that this knowledge could open the door to designing entirely new receptors tailored for the treatment of diseases.
“We could engineer receptors with tailored selectivity and signaling properties for applications in biosensors, chemogenetics, and gene therapy,” says Nour Aldin Kahlous, PhD Student in the Carlsson group and one of the three shared first authors.
