1i5r: Difference between revisions
New page: left|200px<br /> <applet load="1i5r" size="450" color="white" frame="true" align="right" spinBox="true" caption="1i5r, resolution 1.6Å" /> '''TYPE 1 17-BETA HYDRO... |
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[[Image:1i5r.gif|left|200px]]<br /> | [[Image:1i5r.gif|left|200px]]<br /><applet load="1i5r" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1i5r" size=" | |||
caption="1i5r, resolution 1.6Å" /> | caption="1i5r, resolution 1.6Å" /> | ||
'''TYPE 1 17-BETA HYDROXYSTEROID DEHYDROGENASE EM1745 COMPLEX'''<br /> | '''TYPE 1 17-BETA HYDROXYSTEROID DEHYDROGENASE EM1745 COMPLEX'''<br /> | ||
==Overview== | ==Overview== | ||
Human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD type 1) | Human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD type 1) catalyzes the final step in the synthesis of active estrogens that stimulate the proliferation of breast cancer cells. Based on the initial premise to make use of the binding energies of both the substrate and cofactor sites, and molecular modeling starting from the enzyme structure, several estradiol-adenosine hybrids were designed and synthesized. Among these hybrids, EM-1745 with a linker of 8-CH2 groups is proved to be the best competitive inhibitor with a Ki of 3.0 +/- 0.8 nM. The crystal structure of the EM-1745 enzyme complex at 1.6 A provides evidence at atomic resolution of strong interactions between both the steroid and cofactor moieties and the enzyme molecule, as illustrated by a deltaA-weighted 2Fo-Fc electron density map contoured at 3.0 delta. The substrate entry loop is further stabilized in this complex compared with previous complexes of the enzyme. These results confirm our initial strategy of combining studies of structural biology and enzyme mechanism in the inhibitor design, which may be applied to other steroidogenic enzymes involved in human diseases. | ||
==About this Structure== | ==About this Structure== | ||
1I5R 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 HYC and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Estradiol_17-beta-dehydrogenase Estradiol 17-beta-dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.62 1.1.1.62] Full crystallographic information is available from [http:// | 1I5R 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=HYC:'>HYC</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Estradiol_17-beta-dehydrogenase Estradiol 17-beta-dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.62 1.1.1.62] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1I5R OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Boivin, P.]] | [[Category: Boivin, P.]] | ||
[[Category: Campbell, R | [[Category: Campbell, R L.]] | ||
[[Category: Lin, S | [[Category: Lin, S X.]] | ||
[[Category: Poirier, D.]] | [[Category: Poirier, D.]] | ||
[[Category: Qiu, W.]] | [[Category: Qiu, W.]] | ||
| Line 27: | Line 26: | ||
[[Category: inhibitor]] | [[Category: inhibitor]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:08:16 2008'' | ||
Revision as of 14:08, 21 February 2008
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TYPE 1 17-BETA HYDROXYSTEROID DEHYDROGENASE EM1745 COMPLEX
OverviewOverview
Human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD type 1) catalyzes the final step in the synthesis of active estrogens that stimulate the proliferation of breast cancer cells. Based on the initial premise to make use of the binding energies of both the substrate and cofactor sites, and molecular modeling starting from the enzyme structure, several estradiol-adenosine hybrids were designed and synthesized. Among these hybrids, EM-1745 with a linker of 8-CH2 groups is proved to be the best competitive inhibitor with a Ki of 3.0 +/- 0.8 nM. The crystal structure of the EM-1745 enzyme complex at 1.6 A provides evidence at atomic resolution of strong interactions between both the steroid and cofactor moieties and the enzyme molecule, as illustrated by a deltaA-weighted 2Fo-Fc electron density map contoured at 3.0 delta. The substrate entry loop is further stabilized in this complex compared with previous complexes of the enzyme. These results confirm our initial strategy of combining studies of structural biology and enzyme mechanism in the inhibitor design, which may be applied to other steroidogenic enzymes involved in human diseases.
About this StructureAbout this Structure
1I5R is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Estradiol 17-beta-dehydrogenase, with EC number 1.1.1.62 Full crystallographic information is available from OCA.
ReferenceReference
A concerted, rational design of type 1 17beta-hydroxysteroid dehydrogenase inhibitors: estradiol-adenosine hybrids with high affinity., Qiu W, Campbell RL, Gangloff A, Dupuis P, Boivin RP, Tremblay MR, Poirier D, Lin SX, FASEB J. 2002 Nov;16(13):1829-31. Epub 2002 Sep 5. PMID:12223444
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