Raloxifene structure

Type I antiestrogens are competitive inhibitors of the binding of estrogens to ER. As demonstrated for raloxifene, these compounds seem to form a complex with the ER that retains partial transcription activity as a result of imperfect changes in the tertiary structure of the complex (Brzozowski et al. 

Members of the different SERM families bind to the ligand-binding domain (LBD) of the ER, whose particular crystal structure has been revealed for estradiol and for raloxifene (Brzozowski et al. 1997). Once inserted into the binding cavity, estradiol makes direct hydrogen bonds bewteen its A-ring and... 

Fig. 4. Positioning of helix H12 is shown in (a) for the ER LBD-E2 complex and in (b) for the ER LBD-raloxifene complex. H12 is drawn as cylinder (a = E2 complex), (b = raloxifene complex). Dotted lines indicate unmodeled regions of the structures. Hydrophobic residues located in the groove between H3 and H5 and Lys 382 (K362) are depicted in space-filling form. The locations of Asp 538, Glu 542, and Asp 545 are drawn as spheres, along with the helices that interact with H12 in the two complexes (Brzozowski etal., 1997).

Fig. 1.7 Structure of the complex between ER-a (gray) and the selective antagonist raloxifene (solid spheres). In this structure, solved in the absence of a co-repressor peptide, helix-12 (bold) occupies the groove normally occupied by the LxxLL motif of co-activator peptides. From PDB entry 1ERR.

There also exist a class of ligands referred to as SERMs (selective estrogen receptor modulators) that display tissue-selective pharmacology [13]. Raloxifene and tamoxifen are two clinically used SERMs for which structures are available. Crystal structures of the estrogen receptor bound to different ligands (estradiol, tamoxifen, or raloxifene) reveal that ligands of different sizes and shapes induce a spectrum of receptor conformational states. These states can be interpreted by the cellular complexion of co-regulators and the environment of the local promoter of... 

The three-dimensional structure of the ER was resolved by Brzozowski et al. [61]. Four additional X-ray structures of the receptor liganded with different molecules - estradiol, diethylstilbestrol, a nonsteroidal stilben derivative, and two antagonists raloxifen and 4-hydroxytamoxifen - were also solved [61, 62]. The availability of several structurally diverse structures bound to the active site of the receptor provided important experimental information detailing the molecular alignment of the studied molecules. 

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