Ala307Thr variation modulates FSHR structure and impairs its binding affinity for FSH: Implications in polycystic ovarian syndrome

Follicle‐stimulating hormone receptor (FSHR) belongs to the family of G‐protein coupled receptors and acts as a cognate receptor for follicle‐stimulating hormone (FSH). Among the various polymorphic changes reported in FSHR, rs6165 polymorphism leading to Ala307Thr variation in the extracellular domain of the FSHR (FSHRED) is widely reported. Therefore we attempted to evaluate the functional implications of this variation by studying its effects on FSHRED structure as well as FSH binding. Our atomic‐scale investigations reveal that the hinge region, a key hormone interaction site in the extracellular domain of Wt FSHR, exhibits significantly more flexibility compared with the variant structure. Moreover, the Wt receptor in complex with FSH was observed to form a pocket‐like structure in its hinge region whereas such a structure was not detected in the variant. The study further reveals that the key residue, sTyr335, required for FSH recognition and FSHR activation, exhibits lower binding free energy in the variant structure as compared to the Wt. In conclusion, our results point out that Ala307Thr variation leads to structural and conformational anomalies in FSHRED which may alter its FSH binding and affect its activation. Significance statement Follicle‐stimulating hormone receptor (FSHR) Ala307Thr genotype is highly prevalent in ovarian disorders like polycystic ovary syndrome (PCOS) and premature ovarian failure. However, the molecular mechanism by which this variation affects FSHR signalling and plays a pathogenic role in PCOS or other ovarian disorders continues to remain obscure. The findings of this study provide evidence that the Ala307Thr variation not only affects FSHR conformation and activation but also decreases its binding affinity for follicle‐stimulating hormone. Hence FSHR Ala307Thr genotype should be considered a risk factor for PCOS and other ovarian disorders.