1UOM

The Structure of Estrogen Receptor in Complex with a Selective and Potent Tetrahydroisochiolin Ligand.

Summary for 1UOM

• Entry DOI: 10.2210/pdb1uom/pdb
• Related: 1A52 1AKF 1ERE 1ERR 1G50 1GWQ 1GWR 1HCP 1HCQ 1L2I 1QKT 1QKU 3ERD 3ERT
• Descriptor: ESTROGEN RECEPTOR, 2-PHENYL-1-[4-(2-PIPERIDIN-1-YL-ETHOXY)-PHENYL]-1,2,3,4-TETRAHYDRO-ISOQUINOLIN-6-OL (3 entities in total)
• Functional Keywords: selective estrogen receptor modulators, serm, receptor, transcription regulation, dna-binding, nuclear protein, zinc-finger, steroid-binding, phosphorylation, polymorphism 3d-structure, alternative splicing
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Isoform 1: Nucleus. Isoform 3: Nucleus: P03372
• Total number of polymer chains: 1
• Total formula weight: 29400.59

Authors

Stark, W.,Bischoff, S.F.,Buhl, T.,Fournier, B.,Halleux, C.,Kallen, J.,Keller, H.,Renaud, J. (deposition date: 2003-04-11, release date: 2003-07-03, Last modification date: 2023-12-13)

Primary citation

Renaud, J.,Bischoff, S.F.,Buhl, T.,Floersheim, P.,Fournier, B.,Halleux, C.,Kallen, J.,Keller, H.,Schlaeppi, J.-M.,Stark, W.
Estrogen Receptor Modulators: Identification and Structure-Activity Relationships of Potent Eralpha-Selective Tetrahydroisoquinoline Ligands
J.Med.Chem., 46:2945-, 2003

PubMed Abstract: 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.

PubMed: 12825935
DOI: 10.1021/JM030086H

Experimental method

X-RAY DIFFRACTION (2.28 Å)