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The good? The bad? The mutant! Characterization of cancer-related somatic mutations and identification of a selectivity hotspot in adenosine receptor

G protein-coupled receptors (GPCRs), one of the largest families of membrane proteins, are responsive to a diverse set of physiological endogenous ligands including hormones and neurotransmitters.

Wang, X.
20 september 2022
Thesis in Leiden Repository

Due to the various GPCR ligand binding domains present on GPCRs and their sensitivities to a diverse array of ligands, these proteins have shown to be very ‘druggable’ as they are the main target for an estimated 30% of approved drugs. A growing body of evidence shows a prominent role of GPCRs in all phases of cancer with a mutation frequency of approximately 20% in all cancers. Mutations occurring in GPCRs can severely alter their normal function and may ultimately convert their physiological and pathological roles. One particular class of rhodopsin-like GPCRs included in this thesis are the adenosine receptors (ARs). Due to the accumulation of adenosine in the tumor microenvironment, all four subtypes of ARs might be targets for the development of novel approaches for the treatment of cancer. For each of the four subtypes, a number of somatic mutations have been identified in patient isolates. In this thesis, we examined them on receptor activation and ligand binding using reference adenosine receptor ligands, and determined the impact mutations have on these pharmacological readouts.

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