Estrogen Receptor Complexed to Tamoxifin

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I. Introduction

Estrogen Receptor

   The estrogen receptor regulates the differentiation and maintenance of neural, skeletal, cardiovascular, and reproductive tissues in the body.  The ligand binding domain is located in the C-terminus of the protein and binds estrogen and some synthetic materials, including estrogen diethylstilbestrol (DES).  The protein is composed of 12 α-helices and 2 anti-parallel β-sheets.  This model is of  one of the monomers of the estrogen receptor, but in the body, the protein has biological activity when it is a dimer.

For more information see Biochemistry Online: Chapter 8B - BB:  BIOLOGICAL OXIDATION REACTIONS DEHYDROGENASES, MONO- AND DIOXYGENASES, AND OXIDASES


II. General Structure

Wireframe
Backbone
Backbone and sidechains
Cartoon
Cartoon, Hbonds and Wireframe

III. Estrogen Receptor with Tamoxifin

The estrogen receptor can also bind 4-hydroxytamoxifen (tamoxifen), which is a selective estrogen receptor modulators (SERMs).  SERMs act as an antagonist in specific tissue and promoter contexts by mimicking the interactions of the NR box peptide with the ligand binding domain.  The tamoxifin binds differently to the receptor complex by changing the binding domain of α helices 3, 4, 5, and 12.

  The structure of tamoxifen is mostly a hydrophobic hydrocarbon substrate with a hydrophilic hydroxyl group on it.  As a result, most of the binding residues for tamoxifen have non-polar side chains.  The most common residues that interacted with the hydrophobic part of the substrate were glycine, leucine, isoleucine, methionine, alanine, tryptophan, and threonine.  The polar residues that interacted with the polar hydroxyl group of the substrate were glutamic acid, arginine, and histidine.

Tamoxifin
Tamoxifin with protein
Critical binding residues of Tamoxifin binding domain (Met-343, Leu-346, Thr-347, Glu-353, Trp-383, Leu-384, Leu-387, Arg-394, Met-421, Ile-424, Gly-521, His-524, Leu-525).
Critical non-polar binding residues of Tamoxifin binding domain (Met-343, Leu-346, Thr-347, Trp-383, Leu-384, Leu-387, Met-421, Ile-424, Gly-521, Leu-525).
Critical polar binding residues of Tamoxifin binding domain (Glu-353, Arg-394, His-524)
Cartoon with Tamoxifin binding domain

Data for this molecule was obtained from Estrogen Receptor Complexed to DES and tamoxifen. Cell v95 pp.927-937, 1998