1zuc: Difference between revisions
New page: left|200px<br /> <applet load="1zuc" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zuc, resolution 2.00Å" /> '''Progesterone recept... |
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[[Image:1zuc.gif|left|200px]]<br /> | [[Image:1zuc.gif|left|200px]]<br /><applet load="1zuc" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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'''Progesterone receptor ligand binding domain in complex with the nonsteroidal agonist tanaproget'''<br /> | '''Progesterone receptor ligand binding domain in complex with the nonsteroidal agonist tanaproget'''<br /> | ||
==Overview== | ==Overview== | ||
Progesterone receptor (PR) agonists have several important applications in | Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC(50) value of 0.1 nm, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy ( approximately 60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC(50) value of 0.02 nm) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1ZUC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and T98 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 1ZUC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=T98:'>T98</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZUC OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Fensome, A.]] | [[Category: Fensome, A.]] | ||
[[Category: Li, S.]] | [[Category: Li, S.]] | ||
[[Category: Lyttle, C | [[Category: Lyttle, C R.]] | ||
[[Category: Olland, A | [[Category: Olland, A M.]] | ||
[[Category: Unwalla, R | [[Category: Unwalla, R J.]] | ||
[[Category: Wilhem, J.]] | [[Category: Wilhem, J.]] | ||
[[Category: Winneker, R | [[Category: Winneker, R C.]] | ||
[[Category: Wrobel, J.]] | [[Category: Wrobel, J.]] | ||
[[Category: Zhang, P.]] | [[Category: Zhang, P.]] | ||
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[[Category: tanaproget]] | [[Category: tanaproget]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:19:10 2008'' | ||
Revision as of 17:19, 21 February 2008
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Progesterone receptor ligand binding domain in complex with the nonsteroidal agonist tanaproget
OverviewOverview
Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC(50) value of 0.1 nm, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy ( approximately 60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC(50) value of 0.02 nm) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile.
DiseaseDisease
Known disease associated with this structure: Progesterone resistance, 264080 (2) OMIM:[607311]
About this StructureAbout this Structure
1ZUC is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Molecular and pharmacological properties of a potent and selective novel nonsteroidal progesterone receptor agonist tanaproget., Zhang Z, Olland AM, Zhu Y, Cohen J, Berrodin T, Chippari S, Appavu C, Li S, Wilhem J, Chopra R, Fensome A, Zhang P, Wrobel J, Unwalla RJ, Lyttle CR, Winneker RC, J Biol Chem. 2005 Aug 5;280(31):28468-75. Epub 2005 Jun 3. PMID:15937332
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