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spinqualitylabelsall models 1uom, resolution 2.28Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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 with PTI as ligand. Structure known Active Site: PTI. 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

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