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1uom

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[[Image:1uom.gif|left|200px]]
[[Image:1uom.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 1uom |SIZE=350|CAPTION= <scene name='initialview01'>1uom</scene>, resolution 2.28&Aring;
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The line below this paragraph, containing "STRUCTURE_1uom", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=PTI:Pti+Binding+Site+For+Chain+A'>PTI</scene>
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|LIGAND= <scene name='pdbligand=PTI:2-PHENYL-1-[4-(2-PIPERIDIN-1-YL-ETHOXY)-PHENYL]-1,2,3,4-TETRAHYDRO-ISOQUINOLIN-6-OL'>PTI</scene>
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|ACTIVITY=
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{{STRUCTURE_1uom| PDB=1uom | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1uom FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1uom OCA], [http://www.ebi.ac.uk/pdbsum/1uom PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1uom RCSB]</span>
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'''THE STRUCTURE OF ESTROGEN RECEPTOR IN COMPLEX WITH A SELECTIVE AND POTENT TETRAHYDROISOCHIOLIN LIGAND.'''
'''THE STRUCTURE OF ESTROGEN RECEPTOR IN COMPLEX WITH A SELECTIVE AND POTENT TETRAHYDROISOCHIOLIN LIGAND.'''
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[[Category: Renaud, J.]]
[[Category: Renaud, J.]]
[[Category: Stark, W.]]
[[Category: Stark, W.]]
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[[Category: alternative splicing]]
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[[Category: Alternative splicing]]
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[[Category: dna-binding]]
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[[Category: Dna-binding]]
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[[Category: nuclear protein]]
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[[Category: Nuclear protein]]
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[[Category: phosphorylation]]
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[[Category: Phosphorylation]]
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[[Category: polymorphism 3d-structure]]
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[[Category: Polymorphism 3d-structure]]
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[[Category: receptor]]
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[[Category: Receptor]]
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[[Category: selective estrogen receptor modulator]]
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[[Category: Selective estrogen receptor modulator]]
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[[Category: serm]]
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[[Category: Serm]]
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[[Category: steroid-binding]]
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[[Category: Steroid-binding]]
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[[Category: transcription regulation]]
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[[Category: Transcription regulation]]
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[[Category: zinc-finger]]
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[[Category: Zinc-finger]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 11:30:17 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:13:09 2008''
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Revision as of 08:30, 3 May 2008

Image:1uom.gif

Template:STRUCTURE 1uom

THE STRUCTURE OF ESTROGEN RECEPTOR IN COMPLEX WITH A SELECTIVE AND POTENT TETRAHYDROISOCHIOLIN LIGAND.


Overview

As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28 A. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.

About this Structure

1UOM is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands., Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Halleux C, Kallen J, Keller H, Schlaeppi JM, Stark W, J Med Chem. 2003 Jul 3;46(14):2945-57. PMID:12825935 Page seeded by OCA on Sat May 3 11:30:17 2008

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