Chain A: The wild type model is Cartoons, colored Structure. Helices are numbered at their N-termini. Helix 12 is colored gold and labelled "H12A"; EST is Spacefill, colored CPK.
Chain B: The triple Cys->Ser mutant model is Backbone, colored blue. Helix 12 (red) is labelled "H12B" at its C-terminus.
(Residue numbering: Chain A is 300 less, and Chain B is 303 less than the standard ERa numbering.)
The numbered "Highlight" buttons above display details of the EST-binding site and helix 12 pocket on the ER LBD. The following paragraphs briefly describe the displays.
1. Amino Acid Changes. Toggle between the wild type (Cys) and mutant (Ser) displays. In general, the more hydrophilic Ser residues force nearby conformation changes in the protein. For example, the shortening of H3 and H11 are due to the Cys 417 and Cys 530 substitutions respectively. However, the cumulative effect is the radical repositioning of helix 12.2. ERa-EST complex. The principal interacting side chains on chain A are shown, colored CPK; chain colors as above. (Slab on) The same residues in the mutant chain superimpose nearly exactly within the EST binding site. The largest difference is a 0.5 Å shift in the His 524 ring ("H224", here).
H-bond distances are in Å.
Note: the buttons in this group leave the "interacting residues" selected. Thus, any choice of display or color from the Chime menu can be used for additional highlighting.
3. Helix 12 Binding Pockets.
Wild type: This structure is essentially the same as
that seen in other agonist-ER LBD complexes. The H12 and binding site "contacts"
(atoms within 4.5 Å) are colored separately.
Triple mutant: The orientation of H12 in this structure
is nearly the same as that seen in tamoxifen-ER LBD complexes (OHT is an
antagonist.) The H12 and binding site "contacts" (atoms within 4.5 Å)
are colored separately.
4. Hydrogen Bond Network. The wild type (gold Ribbons) conformation is stabilized by a group of side chain and main chain H-bonds that begins with the EST-His 524 interaction. This network is lost in the mutant structure (gray Ribbons), where the same residues are shown as sticks. See Gangloff, et al. Fig. 5c.
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The estrogen receptor structures are described in Gangloff
M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras D. (2001) "Crystal structure
of a mutant hERalpha ligand-binding domain reveals key structural features
for the mechanism of partial agonism". J Biol Chem 276:15059.
PubMed.
[1qku.pdb; 3.2 Å; R = 0.22 and 1qkt.pdb; 2.2 Å; R = 0.22]
Structure alignments were done at the Combinatorial Extension Server.
Additional ER structures:
A. Estrogen Receptora
ERa complexes with bound:
Estradiol (EST),
an agonist.
Raloxifene (RAL),
an antagonist.
Diethylstilbestrol (DES),
an agonist & the NR Box II peptide.
Tamoxifen (OHT),
an antagonist.
(Estradiol (EST),
in an unusual tetrameric structure.)
B. Estrogen Receptorb
ERb complexes with bound:
Genistein (GEN),
a partial agonist.
Raloxifene (RAL),
an antagonist.
C. Structural Alignments Pairwise superimposed comparisons:
ERa
(EST) and ERb (GEN),
ERa vs. ERb
in agonist complexes.
ERa
(RAL) and ERb (RAL),
ERa vs. ERb
in antagonist complexes.
ERa:
DES and OHT, ERa:
agonist vs. antagonist complex.
ERa:
EST, Wild type ER vs. a triple mutant (Helix 12 in the antagonist conformation).
ERa:
EST, The Brzozowski, et al. (1997) vs. Tanenbaum, et al. (1998)
models.
"Helix 12 Gallery":
ERa-EST vs. All five ER-antagonist
(SERM) models.
D. DNA-Binding Domain:
ER-DBD Complex
Base pair & backbone contacts.
