title: Structural and evolutionary analysis of the co-activator binding domain in vertebrate progesterone receptors.
abstract: Biochemical studies show that binding of co-activators to the progesterone receptor [PR] is an important mechanism for regulating of PR-mediated gene transcription. Unfortunately, unlike other steroid receptors, the PR has not been crystalized with a co-activator. Fortunately, the PR has strong structural similarity to the mineralocorticoid receptor [MR] and glucocorticoid receptor [GR], which have been crystalized with co-activators. This similarity allowed us to construct 3D models of the PR with steroid co-activator 1-Box 4 [SRC1-4] and transcriptional intermediary factor 2-Box 3 [TIF2-3], which were extracted from the crystal structures of human MR and GR, respectively. Comparisons of 3D models of human PR with SRC1-4 and TIF2-3 and human MR with SRC1-4 and GR with TIF2-3 identified some unique interactions between the PR and SRC1-4 and TIF2-3. An evolutionary analysis of the sequence of the co-activator binding groove in human PR found strong conservation in terrestrial vertebrates. However, there are some differences between human PR and the PRs in lamprey, shark and fishes. These differences among the PRs and between the PR, MR and GR may have contributed to the evolution of specificity for progestins, mineralocorticoids and glucocorticoids in vertebrates.
authors.affiliation: Department of Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, United States.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Kattoula
authors.affiliation: Department of Medicine, 0693, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, United States. Electronic address: mbaker@ucsd.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Baker
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D056918:Nuclear Receptor Coactivators / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011965:Receptors, Glucocorticoid / Q000737:chemistry; D018161:Receptors, Mineralocorticoid / Q000737:chemistry; D011980:Receptors, Progesterone / Q000737:chemistry* / Q000235:genetics; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D056918:Nuclear Receptor Coactivators; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone
keywords: Progesterone receptor evolution; SRC1; Steroid receptor co-activator 1; TIF2; Transcriptional intermediary factor 2