X-ray Structures of Progesterone Receptor Ligand Binding Domain in Its Agonist State Reveal Differing Mechanisms for Mixed Profiles of 11β-Substituted Steroids

• Published in: The Journal of biological chemistry Vol. 287; no. 24; pp. 20333 - 20343
• Main Authors: Lusher, Scott J., Raaijmakers, Hans C.A., Vu-Pham, Diep, Kazemier, Bert, Bosch, Rolien, McGuire, Ross, Azevedo, Rita, Hamersma, Hans, Dechering, Koen, Oubrie, Arthur, van Duin, Marcel, de Vlieg, Jacob
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-06-2012; American Society for Biochemistry and Molecular Biology
• Subjects: Asoprisnil; Crystallography, X-Ray; Drug Design; Estrenes - chemistry; Humans; Ligands; Mifepristone - chemistry; Nuclear Receptors; Oximes - chemistry; Progesterone; Protein Structure and Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, Progesterone - agonists; Receptors, Progesterone - chemistry; Steroid Hormone Receptor; Structural Biology; Steroid Hormone Receptor; Progesterone; Structural Biology; Nuclear Receptors; Asoprisnil; Drug Design
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.308403

We present here the x-ray structures of the progesterone receptor (PR) in complex with two mixed profile PR modulators whose functional activity results from two differing molecular mechanisms. The structure of Asoprisnil bound to the agonist state of PR demonstrates the contribution of the ligand to increasing stability of the agonist conformation of helix-12 via a specific hydrogen-bond network including Glu723. This interaction is absent when the full antagonist, RU486, binds to PR. Combined with a previously reported structure of Asoprisnil bound to the antagonist state of the receptor, this structure extends our understanding of the complex molecular interactions underlying the mixed agonist/antagonist profile of the compound. In addition, we present the structure of PR in its agonist conformation bound to the mixed profile compound Org3H whose reduced antagonistic activity and increased agonistic activity compared with reference antagonists is due to an induced fit around Trp755, resulting in a decreased steric clash with Met909 but inducing a new internal clash with Val912 in helix-12. This structure also explains the previously published observation that 16α attachments to RU486 analogs induce mixed profiles by altering the binding of 11β substituents. Together these structures further our understanding of the steric and electrostatic factors that contribute to the function of steroid receptor modulators, providing valuable insight for future compound design.
Understanding the molecular basis for the mixed profiles of progesterone receptor (PR) ligands will benefit future drug design.
Two differing mechanisms for the induction of mixed profiles by 11β-steroids are described.
Subtle electrostatic and steric factors explain the differing PR activities of 11β-steroids.
These observations will impact future drug-design strategies for PR and potentially other nuclear receptors.