Section 10
Chapter 9,818

Differential interactions of estrogens and antiestrogens at the 17b-hydroxyl or counterpart hydroxyl with histidine 524 of the human estrogen receptor a

Aliau, S.; Mattras, H.; Richard, E.

Biochemistry (American Chemical Society) 41(25): 79-88


Accession: 009817942

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We investigated the role of H524 of the human estrogen receptor alpha (ERalpha) for the binding of various estrogens [estradiol (E(2)), 3-deoxyestradiol (3-dE(2)), and 17beta-deoxyestradiol (17beta-dE(2))] and antiestrogens [4-hydroxytamoxifen (OHT), RU 39 411 (RU), and raloxifene (Ral)], which possess the 17beta-hydroxyl or counterpart hydroxyl (designated: 17beta/c-OH), with the exception of 17beta-dE(2) and OHT. The work involved a comparison of the binding affinities of these ligands for wild-type and H524 mutant ERs, modified or not with diethyl pyrocarbonate (DEPC), a selective histidine reagent. Alanine substitution of H524 did not significantly change the association affinity constant (relative to OHT) of 17beta-dE(2), whereas those of RU, Ral, E(2), and 3-dE(2) were decreased 3-fold, 14-fold, 24-fold, and 49-fold, respectively. Values of the two ligands available in radiolabeled form (E(2) and OHT) were correlated with the dissociation rate constants, which were increased 250-fold and 2-fold, respectively. The action of DEPC on wild-type ER led to a homogeneous ER population which still bound antiestrogens and 17beta-dE(2) with practically unchanged affinities (less than 4-fold decreases in relative affinity constants), while E(2) and 3-dE(2) displayed markedly decreased affinities (56-fold decrease for E(2)). Conversely, DEPC treatment of H524A mutant ER did not induce marked decreases in the relative affinities of any of the checked compounds (decreases wild-type ER) and very weakly protected H524A ER. Molecular modeling was tentatively used to interpret the biochemical results. Reprinted by permission of the publisher.

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