FIGURE 5 | Evolution of corticosteroid-receptor specificity.

From the following article:

Mechanistic approaches to the study of evolution: the functional synthesis

Antony M. Dean & Joseph W. Thornton

Nature Reviews Genetics 8, 675-688 (September 2007)

doi:10.1038/nrg2160

Mechanistic approaches to the study of evolution: the functional synthesis

a | Timeline for evolution of receptors for three structurally similar steroid hormones. Deoxycorticosterone (DOC) is an ancient vertebrate hormone, whereas aldosterone evolved much later in the tetrapod lineage (as indicated by a black arrow). Modern mineralocorticoid receptors (MRs) can be activated by aldosterone, DOC, and to a lesser extent cortisol. The glucocorticoid receptor (GR) is activated only by cortisol in bony vertebrates. The resurrected ancestral corticoid receptor (AncCR) has MR-like sensitivity to all three hormones. Resurrection of GRs from the ancestral jawed vertebrate (AncGR1) and the ancestral bony vertebrate (AncGR2) show that GR's cortisol specificity evolved in the interval between AncGR1 and AncGR2 (represented as a blue box). Dates from the fossil record are indicated in million of years ago (mya). b | Evolution of GR's cortisol specificity. When two historical replacements from the AncGR1–AncGR2 interval were introduced into the ancestral background, they switched receptor preference from aldosterone to cortisol. Structures of the ancestral proteins show that replacement Ser106Pro causes a kink in the protein backbone, destabilizing the ligand–receptor complex and reducing activation by all ligands; Ser106Pro also repositions site 111, so that replacement Leu111Gln forms hydrogen bonds with the C17-hydroxyl that is unique to cortisol. c | Optimization of the GR phenotype. Three other strict replacements from the same interval abolish function when introduced into AncGR1 with Ser106Pro and Leu111Gln — an unlikely evolutionary path under selection (as indicated by the inhibitory arrow). The ancestral structures identified two other replacements from this interval (out of 37 total) that in isolation have little effect on function, but when combined with the conserved substitutions yield a complete GR-like phenotype (as indicated by the black arrow). Part b reproduced with permission from Ref. 93 © (2007) American Association for the Advancment of Science.

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