Figure 1.
The chemical structures of 17β-estradiol (E2) and the 27 E2 derivatives.
The number of each carbon is labeled next to the atom in the E2 structure. The names of the E2 derivatives were shown in the upper left corner of each frame. The RBA values of the E2 derivatives for ERα and ERβ (data from Table 1 as % of RBA of E2) were shown in the lower right corner of each frame. The numbers were rounded to the nearest integer due to space constraint.
Table 1.
Hydrogen bond lengths (Å) and calculated van der Waals interaction energy (ΔEVDW, kcal/mol) and Coulomb interaction energy (ΔECoulomb, kcal/mol) between estrogen derivatives and the ERα and ERβ LBDs.
Table 2.
Summary of current 3D structures of ERs in complex with various ligands (listed according to the chronological order of the publications).
Figure 2.
The overlay of the ligand-binding domains (LBDs) of ERα and ERβ.
The protein structures were shown in cartoon and colored green and magenta for ERα and ERβ, respectively. E2 molecules were shown in stick and colored blue and red in ERα and ERβ LBD, respectively. α-Helixes and β-sheets in the ER LBDs are labeled according to references [14], [16]. Helix 2 structures are missing in both X-ray structures.
Figure 3.
Overlay of docked and crystal structures of ERα LBD in complex with DES or E2. A
. Superimposed structures of docking result and the crystal structure of ERα LBD in complex with DES. The known crystal structure of ERα LBD in complex with DES (PDB code: 3ERD) was colored in yellow with DES colored in green. The docked DES was colored in orange and ERα LBD was colored in magenta. B. Superimposed structures of docking result and the crystal structure of ERα LBD in complex with E2. The known crystal structure of ERα LBD in complex with E2 (PDB code: 3ERE) was colored in yellow with E2 colored in green. The docked E2 was colored in orange and ERα LBD was colored in magenta. The green dashes indicated the hydrogen bonds formed. All the structures were shown in ball and stick. The atoms involved with hydrogen bond formation were colored according to the atom type, i.e. white for hydrogen, red for oxygen and blue for nitrogen. Hydrogen atoms in other amino acids were not shown.
Figure 4.
Interactions of A-ring derivatives with ERα LBD determined by the molecular docking method.
The green dashes indicate the hydrogen bonds formed. All the structures are shown in ball and stick. The amino acids were colored according to the atom type, i.e. green for carbon, red for oxygen, blue for nitrogen and white for hydrogen. Among the amino acids in the binding site, only E353, R394 and H524 were shown in this figure. E2 was colored in red; 1-methyl-E2 and 4-Methyl-E2 were colored in magenta; 2-OH-E2 and 4-OH-E2 were colored in green; 2-Br-E2 and 4-Br-E2 were colored in blue; 2-MeO-E2 and 4-MeO-E2 were colored in yellow. A. Overlay of all the A-ring derivatives. B. Overlay of E2, 1-methyl-E2, 2-MeO-E2, 2-OH-E2 and 2-Br-E2. C. Overlay of E2, 4-methyl-E2, 4-MeO-E2, 4-OH-E2 and 4-Br-E2.
Figure 5.
Correlation of hydrogen bond length and logRBA of A-ring and B/C-ring derivatives.
The hydrogen bond length data were shown in Table 1. The amino acids shown in the up right corner of each indicated that the hydrogen bonds were formed between 3-hydroxyl groups of the A-ring or B/C-ring derivatives and this specific amino acid in the binding pocket. The curve regression was performed according to the Inverse First Order equation y = y0+ a/x.
Figure 6.
Interactions of B/C-ring (A) and D-ring derivatives (B) with ERα LBD determined by molecular docking.
The green dashes indicate the hydrogen bonds formed. All the structures are shown in ball and stick. The amino acids were colored according to the atom type, i.e. green for carbon, red for oxygen, blue for nitrogen and white for hydrogen. Among the amino acids in the binding site, only E353, R394 and H524 are shown in this figure. E2 was colored in white. The ligands were shown in the following different colors: in panel A, 6α-OH-E2 (yellow), 6β-OH-E2 (orange), 6-keto-E2 (pink), 6-dehydro-E2 (red), 7-dehydro-E2 (magenta), 9(11)-dehydro-E2 (light blue), 11α-OH-E2 (purple) and 11 β-OH-E2 (green); in panel B, E1 (magenta) estriol (16α-OH-E2) (yellow), 16β-OH-E2 (orange), 16-keto-E2 (pink), 17α-OH-E2 (red), 15α-OH-E3 (dark blue), 16α-OH-E1 (light blue), 16-keto-E1 (purple), 16α-OH-E2-17α (brown), 16β-OH-E2-17α (grey).
Figure 7.
Correlation between logRBA and binding energy calculated with equation (1) and data in Table 1.
The correlation coefficient r value is shown in the figure.
Figure 8.
Relationship between the correlation coefficient r and x/y for the estrogen derivatives in Table 1.
For each x/y value, the total binding energy was calculated according to equation (3) and the correlation coefficient r value is calculated by correlating the total binding energy for each chemical with its logRBA. The x/y value is shown in log scale.