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Bifunctional hCG analogs adopt different conformations in LH and FSH receptor complexes
Y Wang1, M P Bernard, W R Moyle
1Department of Obstetrics and Gynecology, Robert Wood Johnson (Rutgers) Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Molecular and Cellular Endocrinology
|February 13, 2001
Summary
Bifunctional gonadotropins, engineered with human follitropin (hFSH) and human chorionic gonadotropin (hCG) elements, bind both lutropin receptor (LHR) and follitropin receptor (FSHR). These analogs adopt distinct receptor-binding conformations, unlike native hormones.
Area of Science:
- Reproductive endocrinology
- Molecular biology
- Protein engineering
Background:
- Human reproduction relies on specific hormone-receptor interactions: follitropin (hFSH) with FSH receptor (FSHR), and lutropin (hLH)/choriogonadotropin (hCG) with LHR.
- Native gonadotropins exhibit distinct receptor specificities.
Purpose of the Study:
- To investigate the conformational basis of bifunctional gonadotropin analogs that bind both FSHR and LHR.
- To understand how engineered substitutions influence receptor binding and conformation.
Main Methods:
- Antibody probes were used to compare conformations of bifunctional analogs.
- Conformations were analyzed before and after complexation with FSHR and LHR.
Main Results:
- Substitution of hFSH residues created bifunctional analogs binding both FSHR and LHR.
- A distant, conformation-sensitive region was altered by substitutions and further by FSHR binding.
- Bifunctional ligands bind both receptors in similar orientations, suggesting conserved binding surfaces.
Conclusions:
- Bifunctional gonadotropins can adopt distinct 'lutropin' and 'follitropin' conformations.
- Receptor interactions accentuate these conformational changes, unlike native hCG or hFSH.