4A2J

PR X-Ray structures in agonist conformations reveal two different mechanisms for partial agonism in 11beta-substituted steroids

Summary for 4A2J

• Entry DOI: 10.2210/pdb4a2j/pdb
• Related: 1A28 1E3K 1SQN 1SR7 1ZUC 2C7A 2W8Y 3ZR7 3ZRA 3ZRB 4A2K 4APU
• Descriptor: PROGESTERONE RECEPTOR, 4-[(11BETA,17BETA)-17-METHOXY-17-(METHOXYMETHYL)-3-OXOESTRA-4,9-DIEN-11-YL]BENZALDEHYDE OXIME, SULFATE ION, ... (4 entities in total)
• Functional Keywords: transcription, partial agonist
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus. Isoform A: Nucleus. Isoform 4: Mitochondrion outer membrane : P06401
• Total number of polymer chains: 2
• Total formula weight: 60931.42

Authors

Lusher, S.J.,Raaijmakers, H.C.A.,Bosch, R.,Vu-Pham, D.,McGuire, R.,Oubrie, A.,de Vlieg, J. (deposition date: 2011-09-27, release date: 2012-04-04, Last modification date: 2024-05-08)

Primary citation

Lusher, S.J.,Raaijmakers, H.C.,Vu-Pham, D.,Kazemier, B.,Bosch, R.,McGuire, R.,Azevedo, R.,Hamersma, H.,Dechering, K.,Oubrie, A.,van Duin, M.,de Vlieg, J.
X-ray structures of progesterone receptor ligand binding domain in its agonist state reveal differing mechanisms for mixed profiles of 11 beta-substituted steroids.
J. Biol. Chem., 287:20333-20343, 2012

PubMed Abstract: 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 Glu(723). 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 Trp(755), resulting in a decreased steric clash with Met(909) but inducing a new internal clash with Val(912) 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.

PubMed: 22535964
DOI: 10.1074/jbc.M111.308403

Experimental method

X-RAY DIFFRACTION (2 Å)