1i5r: Difference between revisions

Revision as of 19:36, 2 May 2008

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. 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 Page seeded by OCA on Fri May 2 19:36:38 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
 [[Image:1i5r.gif|left|200px]]
- {{Structure
+<!--
-|PDB= 1i5r |SIZE=350|CAPTION= <scene name='initialview01'>1i5r</scene>, resolution 1.6&Aring;
+The line below this paragraph, containing "STRUCTURE_1i5r", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HYC:O5&#39;-[9-(3,17B-DIHYDROXY-1,3,5(10)-ESTRATRIEN-16B-YL)-NONANOYL]ADENOSINE'>HYC</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[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] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_1i5r|  PDB=1i5r  |  SCENE=  }}
-|RELATEDENTRY=[[1iol|1IOL]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1i5r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1i5r OCA], [http://www.ebi.ac.uk/pdbsum/1i5r PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1i5r RCSB]</span>
-}}
 '''TYPE 1 17-BETA HYDROXYSTEROID DEHYDROGENASE EM1745 COMPLEX'''
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 [[Category: Qiu, W.]]
 [[Category: 17beta-hydroxysteroid]]
-[[Category: dehydrogenase]]
+[[Category: Dehydrogenase]]
-[[Category: hybrid]]
+[[Category: Hybrid]]
-[[Category: inhibitor]]
+[[Category: Inhibitor]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May  2 19:36:38 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 21:15:02 2008''