Tamoxifen, conformation

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... 

A solution structure of a duplex containing an adenosine N -amino adduct of the trans (lOR)-tetrahydrobenzo [a] pyrene shows that the hydrocarbon is intercalated into the duplex on the 5 -side of the modified base. From 2D exchange data, it can be observed that the modified base inter-converts between the usual anti-conformation into the less populated syn-conformation. The lOS isomer, however, adopts a syn conformation as the major conformer. The solution structure of a 5-cis-tamoxifen-N -guanine adduct in the middle of an 11-mer duplex has been solved. The lesion is accommodated in a widened minor groove without disruption of the neighbouring base pairs, though the helix axis is bent by 30° away from the minor groove adduct site. 

Dewhirst, M.W. and McDonnell, D.P. (2001) Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor. Cancer Research, 61,... 

Figure 5.12 Hydrogen-bond interactions between 4-OH-tamoxifen and ERa. Hydrogen-bond intermolecular interactions of 4-OH-tamoxifen cocomplexed with human ERa LBD usingtheX-raycrystallographicstructure3ERT at 1.9-A resolution [44] are shown. The conformation was visualized using 3D-Mol...

Raloxifene acts as a partial agonist in bone but does not stimulate endometrial proliferation in postmenopausal women. Presumably this is due to some combination of differential expression of transcription factors in the two tissues and the effects of this SERM on ER conformation. Raloxifene induces a configuration in ER a that is distinct from that of tamoxifen-ER (3, suggesting that a different set of coactivators/corepressors may interact with ER-raloxifene compared to ER-tamoxifen. 

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