Directing luteinising hormone receptor activity in vivo: A convergent approach to study GPCR molecular complexes

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Recent technological developments have illuminated how G protein-coupled receptors (GPCRs) are intricately organized from the subcellular to atomic level; exhibiting a multiplicity in conformational states and protein microenvironments. These developments also inform the study of GPCR homomers and heteromers; addressing fundamental mechanisms in how such complexes are allosterically modulated and their coupling to its signalling machinery. Our studies with a GPCR key in reproduction and pregnancy, the luteinsing hormone receptor (LHR), have integrated super-resolution imaging with modelling to demonstrate LHR forms an array of complexes, from monomer, dimer to a variety of low order oligomers, including heteromers with follicle-stimulating hormone receptor (FSHR). Reorganization of protomers alters signal activity and is likely to be mediated by multiple interfaces. Unpicking the physiological role of these complexes is challenging when applied to LHR in female reproduction, where its functions must be coordinated within a highly interconnected system of somatic and germ cells; the ovarian follicle. Our team of investigators and project partners will apply a trans-disciplinary approach to these fundamental mechanisms, by integrating automated super-resolution imaging with machine learning, computational modelling, chemistry, nanobody technology and biophysical sensors. Employing mouse models expressing HA-tagged LHR and FLAG-FSHR, we will image the organization of LHR complexes, with FSHR and its signal machinery, in follicular systems. Protomer reorganization during follicle maturation, and by receptor nanobodies and small molecules that induce distinct conformational and signalling states, will also be applied. Modelling of follicular LHR complexes will identify interfaces for chemical disruption. We will characterise the impact of disrupting or modifying highly defined receptor complexes on classical physiological roles of LH in both mouse and human systems.