Project Reference: TRG27-PHA-MM1

Project title: Receptor activation vs signal scavenging: unravelling the structural rules and exploring the therapeutic potential

Project outline

G protein coupled receptors (GPCRs) are an extensive family of proteins found across human tissues. Individual family members detect specific signals reaching the cell membrane and convey their messages to intracellular partners that activate a variety of physiological responses. By doing so, they regulate key processes including vision, neurotransmission, metabolism, and immunity. When it comes to immune responses, GPCRs can sense signals in the form of chemokine peptides in a complex many-to-many relationship to regulate immune cell migration and function. However, although most receptors capable of sensing chemokines elicit an intracellular response, other receptors have been found to function as ‘scavengers’, sequestering chemokines inside the cell to regulate signalling tone. To date, we still do not fully understand how sequence and structure determine whether a receptor will signal or scavenge upon encountering a chemokine. Additionally, some scavengers have recently been found to bind other GPCR signals, like endogenous opioid peptides, both complicating the picture and opening new exciting avenues to design antagonists targeting scavengers to boost receptor signalling in disease indications like chronic pain. This systems pharmacology project will leverage structural bioinformatics, molecular dynamics, GPCR interactomics, and spatial transcriptomics analyses to unravel key questions on receptor signalling and modulation: a) Which features discriminate chemokine GPCRs from scavengers? b) How does receptor promiscuity towards diverse endogenous ligands correlate to their sequence and structural variation across species and in the human population? c) What can receptor co-expression tell us about the functional crosstalk between receptors with different signalling capabilities but sharing the same endogenous ligands? And c) Can we leverage this knowledge to identify new scavengers or to design receptor-specific antagonists of therapeutic interest?

Principal Supervisor

Dr Maria Marti Solano

Email address: mm2402@cam.ac.uk

Department / Partner Institute: Pharmacology

Website: https://www.phar.cam.ac.uk/research/marti

BBSRC strategic theme

Bioscience for an integrated understanding of health