Perspective evaluates steroid binding mechanisms in adhesion GPCRs, suggesting significant pharmacological implications.
Emerging evidence suggests steroids may act as generalizable ligands for adhesion GPCRs, a receptor class with considerable pharmacological potential. While most studies have focused on the ADGR‘G' subfamily, recent cryo‐EM structures of the androgens 5α‐dihydrotestosterone (5α‐DHT) and methenolone bound to ADGRD1 revealed a putative steroid‐binding pocket and enabled the rational design of a selective synthetic agonist. This perspective considers the broader significance of these findings amid some debate about the reproducibility and physiological relevance of steroid binding to adhesion GPCRs, reviewing all structural evidence and presenting comparative docking and homology modeling to evaluate conserved features and the plausibility of a shared recognition mechanism.
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Fleming et al. (2026) studied this question.
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