Co-activator binding

The proposed role of agonists is to stabilize a precise conformation of the estrogen receptor that allows for productive dimerization and co-activator binding. The structures of agonist-bound NHRs reveal that helix-12 folds over the ligand into a position that stabilizes recruitment of a co-activator. 

Coactivators enhancing the transcriptional activity of steroid hormone receptors activators include SRC-1 (steroid-receptor co-activator 1) or TEF2 (transcriptional intermediary factor 2), which are recruited by the DNA/ steroid hormone receptor complex. Their main role is to attract other transcriptional coactivators with histone acetyltransferase activity in order to decondense chromatin and allow for the binding of components of the general transcription apparatus. 

Hayashi Y (2000) The molecular genetics of recurring chromosome abnormalities in acute myeloid leukemia [In Process Citation]. Semin Hematol 37 368-380 Heery DM, Kalkhoven E, Hoare S, Parker MG (1997) A signature motif in transcriptional co-activators mediates binding to nuclear receptors [see comments]. Nature 387 733-736 Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto M, Ohki M, Hayashi Y (1997) Adenoviral E 1 A-associated protein p300 is involved in acute myeloid leukemia with t(ll 22)(q23 ql3). Blood 90 4699-4704... 

It was previously shown by our group that CO can bind to the active site at the level of both the Nig-S and the Nia-C states. Here we discovered, however, that CO can very rapidly (within 10 ms) reach the active site, but cannot bind to enzyme in the Nig-C state in the absence of light. Binding occurs only upon illumination. This conld even be demonstrated in a frozen enzyme solution (at temperatures below -80°C) by a cycle of illumination and dark adaptation. Based on these findings we conclude that CO does not bind to Nia-C because of the low electron density on Ni (Fig. 7.9). 

The initial FTIR studies (Bagley et al. 1994) also demonstrated binding of CO to the active site, at that time still believed to consist of nickel only. At the present level of understanding of the active Ni-Fe site, these data indicate that the 2060 cm band of the externally added CO is best interpreted as CO binding (end-on) to nickel and not to iron. A higher frequency is expected for binding to iron (like that of the internal CO bound to iron), and vibrational interaction with the internal CO would be expected as well. None of the inactive states can bind CO activation is absolutely required (Bagley et al. 1995). Both EPR and FTIR studies indicate that it is the Nia-S state that binds CO best. Under 1 bar of CO, active enzyme is completely in the Nia-S-CO state the Fe-S clusters in this active (but inhibited) enzyme can be reduced or oxidized, without any effect on the status of the active site (Surerus et al. 1994). 

As indicated in Figure 3.2, this is probably just the binding of hydrogen (presumably as -1- H ) to the active site at some distance from nickel. This binding induces the oxidation of the nickel center (Ni Ni ), whereby the electron initially enters the proximal Fe-S cluster. CO can bind to the divalent nickel in the Nia-S state and thereby fixes the active site in the Nia-S-CO state ... 

Enzymes that are involved in steroid hormone biosynthesis or in steroid metabolism are also targets of anti-hormonal therapy. Recently, it was discovered that certain co-factors modulate the signalling of steroid hormone receptors in a tissue-selective fashion. By binding the receptor ligand complex, these co-activators and co-repressors are capable of either activating or repressing transcription, respectively [5j. 

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