Steroid signaling: ligand-binding promiscuity, molecular symmetry, and the need for gating.
Steroid/sterol-binding receptors and enzymes are remarkably promiscuous in the range of ligands they can bind to and, in the case of enzymes, modify - raising the question of how specific receptor activation is achieved in vivo. Estrogen receptors (ER) are modulated by 27-hydroxycholesterol and 5α-androstane-3β,17β-diol (Adiol), in addition to estradiol (E2), and respond to diverse small molecules such as bisphenol A. Steroid-modifying enzymes are also highly promiscuous in ligand binding and metabolism. The specificity problem is compounded by the fact that the steroid core (hydrogenated cyclopentophenanthrene ring system) has several planes of symmetry. Ligand binding can be in symmetrical East-West (rotation) and North-South (inversion) orientations. Hydroxysteroid dehydrogenases (HSDs) can modify symmetrical 7 and 11, also 3 and 17/20, positions, exemplified here by yeast 3α,20β-HSD and mammalian 11β-HSD and 17β-HSD enzymes. Faced with promiscuity and symmetry, other strategies are clearly necessary to promote signaling selectivity in vivo. Gating regulates hormone access via enzymes that preferentially inactivate (or activate) a subclass of ligands, thereby governing which ligands gain receptor access - exemplified by 11β-HSD gating cortisol access to the mineralocorticoid receptor, and P450 CYP7B1 gating Adiol access to ER. Counter-intuitively, the specificity of steroid/sterol action is achieved not by intrinsic binding selectivity but by the combination of local metabolism and binding affinity.
State University of Pushchino, Prospekt Nauki, Pushchino 142290, Moscow Region, Russia; Pushchino Branch of the Institute of Bio-Organic Chemistry, Russian Academy of Sciences, Pushchino 142290, Moscow Region, Russia; Pieta Research, PO Box 27069, Edinburgh EH10 5YW, UK. Electronic address: rlathe@pieta-research.org.
Richard
R
Lathe
State University of Pushchino, Prospekt Nauki, Pushchino 142290, Moscow Region, Russia; Pushchino Branch of the Institute of Bio-Organic Chemistry, Russian Academy of Sciences, Pushchino 142290, Moscow Region, Russia; Biomedical Centre for Research Education and Innovation (CREI), Skolkovo Institute of Science and Technology, 143025 Skolkovo, Russia; Queens Medical Research Institute, University of Edinburgh, Little France, Edinburgh EH16 4TJ, UK. Electronic address: ykotelev@staffmail.ed.ac.uk.
Yuri
Y
Kotelevtsev
D001665:Binding Sites; D008024:Ligands; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013256:Steroids / Q000737:chemistry* / Q000378:metabolism*
D008024:Ligands; D010455:Peptides; D011506:Proteins; D013256:Steroids
Ligand-binding; Promiscuity; Symmetry