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<P class=MsoNormal style="MARGIN: 0cm -4.05pt 0pt 0cm; TEXT-ALIGN: center"
align=center><A name=OLE_LINK2><STRONG><SPAN lang=ES-AR
style="COLOR: black; FONT-FAMILY: Arial; mso-ansi-language: ES-AR"><FONT
size=3>Seminarios del Dpto. de Química Inorgánica, Analítica y Química Física /
INQUIMAE</FONT></SPAN></STRONG></A><SPAN style="mso-bookmark: OLE_LINK2"><SPAN
style="FONT-SIZE: 10pt; FONT-FAMILY: Arial"><?xml:namespace prefix = o ns =
"urn:schemas-microsoft-com:office:office" /><o:p></o:p></SPAN></SPAN></P>
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align=center><FONT size=3><SPAN style="mso-bookmark: OLE_LINK2"><STRONG><SPAN
lang=ES-AR
style="COLOR: black; FONT-FAMILY: Arial; mso-ansi-language: ES-AR">FCEyN -
Universidad de Buenos Aires</SPAN></STRONG></SPAN><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN
style="FONT-FAMILY: Arial"><o:p></o:p></SPAN></SPAN></FONT></P>
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align=center><SPAN style="mso-bookmark: OLE_LINK2"></SPAN><A
href="http://www.qi.fcen.uba.ar/es"><FONT size=3><SPAN
style="mso-bookmark: OLE_LINK2"><B><SPAN lang=ES-AR
style="FONT-FAMILY: Arial; mso-ansi-language: ES-AR">http://www.qi.fcen.uba.ar/es</SPAN></B></SPAN><SPAN
style="mso-bookmark: OLE_LINK2"></SPAN></FONT></A><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN
style="FONT-FAMILY: Arial"><o:p></o:p></SPAN></SPAN></P>
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align=center><SPAN style="mso-bookmark: OLE_LINK2"><SPAN
style="FONT-FAMILY: Arial"><FONT
size=3> <o:p></o:p></FONT></SPAN></SPAN></P>
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lang=PT-BR
style="COLOR: black; FONT-FAMILY: Arial; mso-ansi-language: PT-BR">2do.
Cuatrimestre, 2006</SPAN></STRONG></SPAN><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN lang=PT-BR
style="FONT-FAMILY: Arial; mso-ansi-language: PT-BR"><o:p></o:p></SPAN></SPAN></FONT></P>
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style="FONT-FAMILY: Arial; mso-ansi-language: PT-BR"><o:p><FONT
size=3> </FONT></o:p></SPAN></SPAN></P>
<P class=MsoNormal
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align=center><SPAN style="mso-bookmark: OLE_LINK2"><SPAN lang=PT-BR
style="FONT-FAMILY: Arial; mso-ansi-language: PT-BR"><FONT
size=3> <o:p></o:p></FONT></SPAN></SPAN></P>
<P class=MsoNormal
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align=center><SPAN style="mso-bookmark: OLE_LINK2"><STRONG><SPAN
style="FONT-SIZE: 14pt; COLOR: black; FONT-FAMILY: Arial">Viernes 15 de
Septiembre, 13.00h</SPAN></STRONG></SPAN><SPAN
style="mso-bookmark: OLE_LINK2"><B><SPAN
style="COLOR: black; FONT-FAMILY: Arial"><BR><STRONG><SPAN
style="FONT-FAMILY: Arial"><FONT size=3>Aula Seminarios, DQIAyQF-
INQUIMAE<o:p></o:p></FONT></SPAN></STRONG></SPAN></B></SPAN></P>
<P class=MsoNormal
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align=center><FONT size=3><SPAN style="mso-bookmark: OLE_LINK2"><STRONG><SPAN
lang=ES-AR
style="COLOR: black; FONT-FAMILY: Arial; mso-ansi-language: ES-AR">Ciudad
Universitaria, Pab. II, Piso 3</SPAN></STRONG></SPAN><SPAN
style="mso-bookmark: OLE_LINK2"><B><U><SPAN
style="mso-bidi-font-size: 10.0pt"><o:p></o:p></SPAN></U></B></SPAN></FONT></P>
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style="mso-bookmark: OLE_LINK2"><B><U><SPAN
style="mso-bidi-font-size: 10.0pt"><o:p><SPAN
style="TEXT-DECORATION: none"><FONT face="Times New Roman"
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<P class=MsoNormal style="MARGIN: 0cm 0cm 0pt"><SPAN
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<H2 style="MARGIN: 0cm 0cm 0pt; TEXT-ALIGN: center" align=center><SPAN
style="mso-bookmark: OLE_LINK2"><B style="mso-bidi-font-weight: normal"><SPAN
lang=PT-BR
style="FONT-SIZE: 14pt; FONT-STYLE: normal; FONT-FAMILY: Arial; mso-ansi-language: PT-BR; mso-bidi-font-style: italic">Munir
S. Skaf<o:p></o:p></SPAN></B></SPAN></H2>
<H2 style="MARGIN: 0cm 0cm 0pt; TEXT-ALIGN: center" align=center><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN lang=PT-BR
style="FONT-SIZE: 14pt; FONT-STYLE: normal; FONT-FAMILY: Arial; mso-ansi-language: PT-BR; mso-bidi-font-style: italic">Insituto
de Química. </SPAN></SPAN><SPAN style="mso-bookmark: OLE_LINK2"><SPAN
style="FONT-SIZE: 14pt; FONT-STYLE: normal; FONT-FAMILY: Arial; mso-bidi-font-style: italic">UNICAMP,
Campinas, Brasil<o:p></o:p></SPAN></SPAN></H2>
<H1 style="MARGIN: 0cm 0cm 0pt; TEXT-ALIGN: center" align=center><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN lang=EN-GB
style="FONT-SIZE: 14pt; FONT-FAMILY: Arial; mso-ansi-language: EN-GB"><o:p> </o:p></SPAN></SPAN></H1>
<H1 style="MARGIN: 0cm 0cm 0pt; TEXT-ALIGN: center" align=center><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN lang=EN-GB
style="FONT-SIZE: 14pt; FONT-FAMILY: Arial; mso-ansi-language: EN-GB"><o:p> </o:p></SPAN></SPAN></H1>
<H1 style="MARGIN: 0cm 0cm 0pt; TEXT-ALIGN: center" align=center><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN lang=EN-GB
style="FONT-SIZE: 14pt; FONT-FAMILY: Arial; mso-ansi-language: EN-GB">Ligand
Dissociation from Nuclear Receptors: Insights from Molecular
Dynamics<o:p></o:p></SPAN></SPAN></H1>
<P class=MsoNormal style="MARGIN: 0cm 0cm 0pt"><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN lang=EN-GB
style="mso-ansi-language: EN-GB"><o:p><FONT face="Times New Roman"
size=3> </FONT></o:p></SPAN></SPAN></P>
<P class=MsoNormal style="MARGIN: 0cm 0cm 0pt"><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN lang=EN-GB
style="mso-ansi-language: EN-GB"><o:p><FONT face="Times New Roman"
size=3> </FONT></o:p></SPAN></SPAN></P>
<P class=MsoNormal style="MARGIN: 0cm 0cm 0pt; TEXT-ALIGN: justify"><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN lang=EN-GB
style="mso-ansi-language: EN-GB"><FONT size=3><FONT
face="Times New Roman">Nuclear receptors (NR) comprise a family of key proteins
responsible for regulating gene transcription. Transcriptional activation
(deactivation) mechanisms are triggered by the binding (unbinding) of small
hydrophobic molecules (hormones) to the ligand binding domain (LBD) of nuclear
receptors. The NR superfamily includes receptors for thyroid hormone, retinoids,
steroids, vitamin D, xenobiotics, fatty acids, bile acids and cholesterol
derivatives, and orphan receptors for which ligands have not been identified.
NRs play widespread roles in development, homeostasis and disease, and,
consequently, are major targets for pharmaceutical development. Nuclear Receptor
(NR) ligands occupy a pocket that lies within the core of the NR ligand binding
domain (LBD), and most NR LBDs lack obvious entry/exit routes upon the protein
surface. Thus, significant NR conformational rearrangements must accompany
ligand binding and release. The precise nature of these processes, however,
remains poorly understood. In this talk, I will present results of Locally
Enhanced Sampling (LES) Molecular Dynamics computer simulations which has been
utilized to predict molecular motions of X-ray structures of thyroid hormone
receptor (TR) LBDs and determine events that permit ligand escape. We find that
the natural ligand (T3) dissociates from the TRa1 LBD along three competing
pathways (Paths I-III) involving different LBD regions. We also propose that
different escape paths are preferred in different situations, implying that it
will be possible to design NR ligands that only associate stably with their
cognate receptors in specific cellular contexts. The relative importance of
putative pathways I-III is investigated using Steered Molecular Dynamics
simulations. Our results show that the likeliest route for ligand dissociation
from TR involves the highly mobile region at the bottom of the LBD (Path III),
and that this mechanisms is favored by the replacement of hydrophilic
interactions of the polar end of the ligand with the protein by ligand-water
(external) interactions. Further analysis of the role played by surrounding
water molecules suggests effective strategies for developing novel, high
affinity, TR ligands. Some results concerning ligand selectivity towards
different protein isoforms will also be
presented.<o:p></o:p></FONT></FONT></SPAN></SPAN></P>
<P class=MsoNormal style="MARGIN: 0cm -4.05pt 0pt 0cm; TEXT-ALIGN: center"
align=center><SPAN style="mso-bookmark: OLE_LINK2"><SPAN lang=EN-GB
style="mso-ansi-language: EN-GB"><BR></SPAN></SPAN><SPAN
style="mso-bookmark: OLE_LINK2"><SPAN
style="FONT-FAMILY: 'ITC Zapf Dingbats'; mso-bidi-font-family: Arial"><FONT
size=3>iiiii</FONT></SPAN></SPAN><SPAN
style="FONT-FAMILY: 'ITC Zapf Dingbats'; mso-bidi-font-family: Arial"><o:p></o:p></SPAN></P></FONT></DIV></BODY></HTML>