Fig. 5: Structural basis of allosteric agonist selectivity for FSHR.

a Structural comparison of Cpd-21f binding pocket in the FSH-FSHR-Gs complex with the Org43553 binding pocket in the CG-LHCGR-Gs complex, and ML-109 binding pocket in the TSH-TSHR-Gs complex. b Structural comparison of the binding pockets in FSHR and LHCGR TMDs. The clashes between ML-109 and the extracellular side of TM6 of FSHR and LHCGR are highlighted in red circles. The shift between FSHR TM6 and TSHR TM6 was measured at residues S594 in FSHR and S646 in TSHR. c, d Concentration-response curves for WT and mutated FSHR. The representative concentration-response curves from three independent experiments were shown. WT refers to wild type receptor; TM6 means swapping of the extracellular portion of FSHR TM6 (residues 591–599) with the corresponding TSHR TM6 region (residues 643–651); TM5/TM6 means the replacement of the extracellular portions of both TM5 and TM6 from FSHR (residues 527–536/591–599) with the corresponding TSHR TM5/TM6 regions (residues 579–588 and 643–651); TM5/TM6/A352E means mutation of A352E in addition to the above TM5/TM6 mutations; TM5/TM6/A352E/H615Y means mutation of H615^7.42Y in addition to the above TM5/TM6/A352E mutations; TM5/TM6/A352E/I411M means mutation of I411^2.53M in addition to the above TM5/TM6/A352E mutations; TM5/TM6/A352E/H615Y/I411M means mutations of H615^7.42Y and I411^2.53M in addition to the above TM5/TM6/A352E mutations. e Structural comparison of the binding pockets in FSHR, LHCGR and TSHR. The clashes between Cpd-21f and residue Y612^7.42 of LHCGR and Y667^7.42 of TSHR are highlighted in red circle. f Concentration-response curves for WT and mutated FSHR. The representative concentration-response curves from three independent experiments were shown. UD, undetectable. Data were shown as mean ± S.E.M. from three independent experiments. Source data are provided as a Source Data file.