Understanding the residue-level interactions that drive molecular recognition and allostery remains a central challenge in modern protein science, particularly as methods to efficiently experimentally profile protein function in a deep, holistic manner have been slow to develop. To address this gap, we develop multi-phenotypic screens for GPCR function and combine them with Deep Mutational Scanning (DMS) to gain a comprehensive understanding of receptor function. Here, we use the μ Opioid Receptor (μOR) as a model system and generate over 1 million measurements of mutational effects on efficacy, potency, and internalization across diverse ligand chemotypes. Our analyses uncovered critical receptor positions dictating ligand recognition as well as allosteric networks governing ligand efficacy and potency. Additionally, we further resolved trafficking motifs in the C-tail that regulate receptor trafficking. By integrating these data, we gained insight into fundamental principles of ligand-receptor interactions and how they percolate down to cellular responses. This technology provides a novel and quantitative lens that will aid in understanding receptor biology and accelerate drug development for GPCRs and beyond.
Howard et al. (Sun,) studied this question.
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