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Steroid structure and function V. A-ring conformation in 17-hydroxy-6 alpha-methylprogesterone.

W L Duax, P D Strong

    Steroids
    |November 1, 1979
    PubMed
    Summary
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    The 6 alpha-methyl group alone does not invert the A-ring in 17-hydroxy-6 alpha-methylprogesterone. Instead, combined 17 alpha-acetoxy and 6 alpha-methyl interactions induce the A-ring inversion crucial for progesterone receptor binding.

    Area of Science:

    • Steroid chemistry
    • Molecular modeling
    • Crystallography

    Background:

    • Progesterone receptor (PR) binding affinity is influenced by steroid molecular conformation.
    • The A-ring conformation of progesterone derivatives is critical for receptor interaction.
    • Previous studies suggested the 6 alpha-methyl group induces A-ring inversion.

    Purpose of the Study:

    • To determine the molecular conformation of 17-hydroxy-6 alpha-methylprogesterone.
    • To compare its conformation with related progesterone derivatives.
    • To elucidate the structural basis for A-ring inversion and its impact on progesterone receptor binding.

    Main Methods:

    • X-ray crystallography was used to determine the precise three-dimensional structure.
    • Comparative analysis of crystal structures of multiple progesterone derivatives.

    Related Experiment Videos

  • Computational analysis to understand substituent effects on ring conformation.

    • Main Results:

    • The 6 alpha-methyl substituent alone does not induce A-ring inversion in 17-hydroxy-6 alpha-methylprogesterone.
    • The inverted A-ring conformation, observed in medroxyprogesterone acetate (MPA), requires both the 17 alpha-acetoxy group and the 6 alpha-methyl group.
    • The 17 alpha-acetoxy group exerts a long-range influence, while the 6 alpha-methyl group interacts directly with the A-ring.

    Conclusions:

    • The 6 alpha-methyl group is insufficient to cause A-ring inversion.
    • A-ring inversion in MPA is a result of synergistic effects between the 17 alpha-acetoxy and 6 alpha-methyl substituents.
    • This conformational change is proposed to be responsible for the high affinity binding of MPA to the progesterone receptor.