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Department of Molecular and Integrative Physiology (J.S., B.S.K.), and Department of Chemistry (J.B., J.A.K.), University of Illinois, Urbana, Illinois 61801
Address all correspondence and requests for reprints to: Dr. Benita S. Katzenellenbogen, University of Illinois, Department of Molecular and Integrative Physiology, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704. E-mail: katzenel{at}life.uiuc.edu.
Although the two subtypes of the human estrogen receptor (ER), ER
and ERß, share only 56% amino acid sequence identity in their ligand binding domain (LBD), the residues that surround the ligand are nearly identical; nevertheless, subtype-selective ligands are known. To understand the molecular basis by which diarylpropionitrile (DPN), an ERß-selective ligand, is able to discriminate between the two ERs, we examined its activity on ER mutants and chimeric constructs generated by DNA shuffling. The N-terminal region of the ERß LBD (through helix 6) appears to be fully responsible for the ERß selectivity of DPN. In fact, a single ER point mutation (L384M) was largely sufficient to switch the DPN response of this ER to that of the ERß type, but residues in helix 3 are also important in achieving the full ERß selectivity of DPN. Using molecular modeling, we found an energetically favorable fit for the S-DPN enantiomer in ERß, in which the proximal phenol mimics the A ring of estradiol, and the nitrile engages in stabilizing interactions with residues in the ligand-binding pocket of ERß. Our findings highlight that a limited number of critical interactions of DPN with the ERß ligand-binding pocket underlie its ER subtype-selective character.
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