1xqc
From Proteopedia
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| - | [[Image:1xqc.gif|left|200px]] | + | [[Image:1xqc.gif|left|200px]] |
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| - | '''X-ray structure of ERalpha LBD bound to a tetrahydroisoquinoline SERM ligand at 2.05A resolution''' | + | {{Structure |
| + | |PDB= 1xqc |SIZE=350|CAPTION= <scene name='initialview01'>1xqc</scene>, resolution 2.05Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=AEJ:(1S)-1-{4-[(9AR)-OCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZIN-2-YL]PHENYL}-2-PHENYL-1,2,3,4-TETRAHYDROISOQUINOLIN-6-OL'>AEJ</scene> | ||
| + | |ACTIVITY= | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''X-ray structure of ERalpha LBD bound to a tetrahydroisoquinoline SERM ligand at 2.05A resolution''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1XQC is a [ | + | 1XQC 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=1XQC OCA]. |
==Reference== | ==Reference== | ||
| - | Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands., Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P, J Med Chem. 2005 Jan 27;48(2):364-79. PMID:[http:// | + | Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands., Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P, J Med Chem. 2005 Jan 27;48(2):364-79. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15658851 15658851] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: nuclear hormone receptor]] | [[Category: nuclear hormone receptor]] | ||
| - | ''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 15:13:12 2008'' |
Revision as of 13:13, 20 March 2008
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| Coordinates: | save as pdb, mmCIF, xml | ||||||
X-ray structure of ERalpha LBD bound to a tetrahydroisoquinoline SERM ligand at 2.05A resolution
Contents |
Overview
We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
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
1XQC is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands., Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P, J Med Chem. 2005 Jan 27;48(2):364-79. PMID:15658851
Page seeded by OCA on Thu Mar 20 15:13:12 2008
