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1uom
From Proteopedia
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| - | [[Image:1uom.gif|left|200px]] | + | [[Image:1uom.gif|left|200px]] |
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| - | '''THE STRUCTURE OF ESTROGEN RECEPTOR IN COMPLEX WITH A SELECTIVE AND POTENT TETRAHYDROISOCHIOLIN LIGAND.''' | + | {{Structure |
| + | |PDB= 1uom |SIZE=350|CAPTION= <scene name='initialview01'>1uom</scene>, resolution 2.28Å | ||
| + | |SITE= <scene name='pdbsite=PTI:Pti+Binding+Site+For+Chain+A'>PTI</scene> | ||
| + | |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> | ||
| + | |ACTIVITY= | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''THE STRUCTURE OF ESTROGEN RECEPTOR IN COMPLEX WITH A SELECTIVE AND POTENT TETRAHYDROISOCHIOLIN LIGAND.''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1UOM is a [ | + | 1UOM is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UOM OCA]. |
==Reference== | ==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:[http:// | + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/12825935 12825935] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: polymorphism 3d-structure]] | [[Category: polymorphism 3d-structure]] | ||
[[Category: receptor]] | [[Category: receptor]] | ||
| - | [[Category: selective estrogen receptor | + | [[Category: selective estrogen receptor modulator]] |
[[Category: serm]] | [[Category: serm]] | ||
[[Category: steroid-binding]] | [[Category: steroid-binding]] | ||
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[[Category: zinc-finger]] | [[Category: zinc-finger]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 14:34:49 2008'' |
Revision as of 12:34, 20 March 2008
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| , resolution 2.28Å | |||||||
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| Coordinates: | save as pdb, mmCIF, xml | ||||||
THE STRUCTURE OF ESTROGEN RECEPTOR IN COMPLEX WITH A SELECTIVE AND POTENT TETRAHYDROISOCHIOLIN LIGAND.
Contents |
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.
Disease
Known diseases associated with this structure: Atherosclerosis, susceptibility to OMIM:[133430], Breast cancer OMIM:[133430], Estrogen resistance OMIM:[133430], HDL response to hormone replacement, augmented OMIM:[133430], Migraine, susceptibility to OMIM:[133430], Myocardial infarction, susceptibility to OMIM:[133430]
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 Thu Mar 20 14:34:49 2008
Categories: Homo sapiens | Single protein | Bischoff, S F. | Buhl, T. | Fournier, B. | Halleux, C. | Kallen, J. | Keller, H. | Renaud, J. | Stark, W. | PTI | Alternative splicing | Dna-binding | Nuclear protein | Phosphorylation | Polymorphism 3d-structure | Receptor | Selective estrogen receptor modulator | Serm | Steroid-binding | Transcription regulation | Zinc-finger
