Asymmetric selectivity at the glycoprotein hormone receptor allosteric site
- 1Independent Researcher
Abstract
Position 7.42 of the glycoprotein hormone receptors has been proposed as the determinant of mutual selectivity between LHCGR and FSHR, but has not been tested reciprocally. We compared the allosteric pockets of LHCGR with Org 43553 (PDB 7FIH) and FSHR with Cpd-21f (PDB 8I2G), and mapped each ligand into the other receptor by transmembrane superposition. Seven of 27 aligned contact positions diverge, a rate not distinguishable from the transmembrane background, and the mapping is markedly asymmetric. Cpd-21f placed in LHCGR makes a 2.31 Å contact with Tyr612, against 3.69 Å for the native His615 contact, and this is the single worst contact in the molecule. Org 43553 placed in FSHR meets no comparable barrier: 21 of 23 native contacts are preserved, burial increases, and the only sequence-driven loss is a hydroxyl-to-methyl van der Waals contact. Position 7.42 therefore excludes FSHR-selective ligands from LHCGR but does not explain why Org 43553 is weaker at FSHR. We further show that the morpholine tail of Org 43553 is buried rather than solvent-exposed and contacts only residues shared between the two receptors, accounting for published structure–activity data in which extensive variation of that tail failed to shift the LH:FSH ratio. A survey of ten orthologs identifies Phe515, the closest divergent contact and the only contact-shell position where LHCGR differs from a residue both paralogs share, as primate-specific; every non-primate examined, including all standard preclinical species, carries the paralog leucine. Finally, this pocket defeats several widely used scoring functions, which rank a reciprocal head-to-tail decoy above the crystallographic pose.
Related
- Uncoupling of the allosteric signalling network in the β₁-adrenergic receptor by a negative allosteric modulator.
- Mechanistic basis of μ-opioid receptor allosteric modulation from molecular simulations
- Pharmacological analysis of negative allosteric modulation of the α7 nicotinic receptor by polyunsaturated free fatty acids
- The cytokine structural homologs IL-1β and IL-1Ra have distinct dynamical character that potentially influence their roles in allosteric regulation of the IL-1 receptor.
- AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity
BibTeX
@misc{nasser2026asymmetric,
title = {{Asymmetric selectivity at the glycoprotein hormone receptor allosteric site}},
author = {Patrick Nasser},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15009727/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009727/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Asymmetric selectivity at the glycoprotein hormone receptor allosteric site
AU - Patrick Nasser
PY - 2026
DA - 2026/10/01
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009727/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009727/v1
AB - Position 7.42 of the glycoprotein hormone receptors has been proposed as the determinant of mutual selectivity between LHCGR and FSHR, but has not been tested reciprocally. We compared the allosteric pockets of LHCGR with Org 43553 (PDB 7FIH) and FSHR with Cpd-21f (PDB 8I2G), and mapped each ligand into the other receptor by transmembrane superposition. Seven of 27 aligned contact positions diverge, a rate not distinguishable from the transmembrane background, and the mapping is markedly asymmetric. Cpd-21f placed in LHCGR makes a 2.31 Å contact with Tyr612, against 3.69 Å for the native His615 contact, and this is the single worst contact in the molecule. Org 43553 placed in FSHR meets no comparable barrier: 21 of 23 native contacts are preserved, burial increases, and the only sequence-driven loss is a hydroxyl-to-methyl van der Waals contact. Position 7.42 therefore excludes FSHR-selective ligands from LHCGR but does not explain why Org 43553 is weaker at FSHR. We further show that the morpholine tail of Org 43553 is buried rather than solvent-exposed and contacts only residues shared between the two receptors, accounting for published structure–activity data in which extensive variation of that tail failed to shift the LH:FSH ratio. A survey of ten orthologs identifies Phe515, the closest divergent contact and the only contact-shell position where LHCGR differs from a residue both paralogs share, as primate-specific; every non-primate examined, including all standard preclinical species, carries the paralog leucine. Finally, this pocket defeats several widely used scoring functions, which rank a reciprocal head-to-tail decoy above the crystallographic pose.
ER -