4apu | pdb_00004apu

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

spinqualitylabelsall models 4apu, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4apu is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: A2K, OR8, SO4 Related: 1a28, 1e3k, 1sqn, 1sr7, 1zuc, 2c7a, 2w8y, 3zr7, 3zra, 3zrb, 4a2j Resources: FirstGlance, OCA, RCSB, PDBsum Function [PRGR_HUMAN] The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor isoform B (PRB) is involved activation of c-SRC/MAPK signaling on hormone stimulation. Isoform A is inactive in stimulating c-Src/MAPK signaling on hormone stimulation. Publication Abstract from PubMed 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 16alpha attachments to RU486 analogs induce mixed profiles by altering the binding of 11beta 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. X-ray Structures of Progesterone Receptor Ligand Binding Domain in Its Agonist State Reveal Differing Mechanisms for Mixed Profiles of 11beta-Substituted Steroids.,Lusher SJ, Raaijmakers HC, Vu-Pham D, Kazemier B, Bosch R, McGuire R, Azevedo R, Hamersma H, Dechering K, Oubrie A, van Duin M, de Vlieg J J Biol Chem. 2012 Jun 8;287(24):20333-43. Epub 2012 Apr 25. PMID:22535964 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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