Abstract
Intracellular variable fragments of heavy‐chain antibody from camelids (intra‐VHH) have been successfully used as chaperones to solve the 3D structure of active G protein‐coupled receptors bound to their transducers. However, their effect on signalling has been poorly explored, although they may provide a better understanding of the relationships between receptor conformation and activity. Here, we isolated and characterized iPRC1, the first intra‐VHH recognizing a member of the large glycoprotein hormone receptor family, the follicle‐stimulating hormone receptor (FSHR). This intra‐VHH recognizes the FSHR third intracellular loop and decreases cAMP production in response to FSH, without altering Gαs recruitment. Hence, iPRC1 behaves as an allosteric modulator and provides a new tool to complete structure/activity studies performed thus far on this receptor.