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Interaction of Follicle‐Stimulating Hormone (FSH) Receptor Binding Inhibitor‐8: A Novel FSH‐Binding Inhibitor, with FSH and its Receptor
Author(s) -
Chitnis Swati S.,
Selvaakumar Chellasamy,
Jagtap Dhanashree D.,
Barnwal Ravi P.,
Chary Kandala V. R.,
Mahale Smita D.,
Nandedkar Tarala D.
Publication year - 2009
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2009.00810.x
Subject(s) - follicle stimulating hormone receptor , follicle stimulating hormone , endocrinology , chemistry , medicine , receptor , hormone , hormone receptor , biology , luteinizing hormone , cancer , breast cancer
Follicle‐stimulating hormone (FSH) receptor binding inhibitor (FRBI‐8) is a novel octapeptide purified from human ovarian follicular fluid. In vitro , it inhibits the binding of FSH to granulosa cells and in vivo , it induces atresia in developing follicles in rodents. This peptide, when administered to marmosets and bonnet monkeys, altered the circulating progesterone levels. This study was carried out to elucidate structure of the FRBI‐8 and understand its mechanism of inhibiting interaction of FSH to its receptors. Homology modeling predicted that the FRBI‐8 adopts a turn and random coil. This is further confirmed by circular dichroism and NMR. Docking studies of the FRBI‐8 with reported FSH–FSHR hormone binding (FSHR HB ) domain complex using zdock algorithm revealed that the FRBI‐8 binds to FSHβL2–FSHR HB binding interface which is otherwise known to be crucial for activation of signal transduction cascade. FRBI‐8 analogs were designed by replacing the acidic amino acid residues at positions 2, 5 and 6 with Ala, individually. Docking studies revealed that D6A mutant (FRBI‐8 D6A ) had a higher binding affinity than the native FRBI‐8. In vitro radioreceptor assay with FRBI‐8 D6A showed 50% lower IC 50 compared with the FRBI‐8, confirming the in silico observations. Thus, the study reveals that both FRBI‐8 and FRBI‐8 D6A interfered with the binding of FSH to its receptor.