2q6j
From Proteopedia
(New page: 200px<br /> <applet load="2q6j" size="450" color="white" frame="true" align="right" spinBox="true" caption="2q6j, resolution 2.700Å" /> '''Crystal Structure ...) |
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| - | [[Image:2q6j.gif|left|200px]]<br /> | + | [[Image:2q6j.gif|left|200px]]<br /><applet load="2q6j" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="2q6j, resolution 2.700Å" /> | caption="2q6j, resolution 2.700Å" /> | ||
'''Crystal Structure of Estrogen Receptor alpha Complexed to a B-N Substituted Ligand'''<br /> | '''Crystal Structure of Estrogen Receptor alpha Complexed to a B-N Substituted Ligand'''<br /> | ||
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==Overview== | ==Overview== | ||
To increase the chemical diversity of bioactive molecules by incorporating, unusual elements, we have examined the replacement of a C=C double bond, with the isoelectronic, isostructural B-N bond in the context of, nonsteroidal estrogen receptor (ER) ligands. While the B-N bond was, hydrolytically labile in the unhindered cyclofenil system, the more, hindered anilino dimesitylboranes, analogs of triarylethylene estrogens, were easily prepared, hydrolytically stable, and demonstrated substantial, affinity for ERs. X-ray analysis of one ERalpha-ligand complex revealed, steric clashes with the para methyl groups distorting the receptor;, removal of these groups resulted in an increase in affinity, potency, and, transcriptional efficacy. These studies define the structural determinants, of stability and cellular bioactivity of a B-N for C=C substitution in, nonsteroidal estrogens and provide a framework for further exploration of, "elemental isomerism" for diversification of drug-like molecules. | To increase the chemical diversity of bioactive molecules by incorporating, unusual elements, we have examined the replacement of a C=C double bond, with the isoelectronic, isostructural B-N bond in the context of, nonsteroidal estrogen receptor (ER) ligands. While the B-N bond was, hydrolytically labile in the unhindered cyclofenil system, the more, hindered anilino dimesitylboranes, analogs of triarylethylene estrogens, were easily prepared, hydrolytically stable, and demonstrated substantial, affinity for ERs. X-ray analysis of one ERalpha-ligand complex revealed, steric clashes with the para methyl groups distorting the receptor;, removal of these groups resulted in an increase in affinity, potency, and, transcriptional efficacy. These studies define the structural determinants, of stability and cellular bioactivity of a B-N for C=C substitution in, nonsteroidal estrogens and provide a framework for further exploration of, "elemental isomerism" for diversification of drug-like molecules. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Atherosclerosis, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Breast cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Estrogen resistance OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], HDL response to hormone replacement, augmented OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Migraine, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Myocardial infarction, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 2Q6J is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with A48 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 2Q6J is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=A48:'>A48</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q6J OCA]. |
==Reference== | ==Reference== | ||
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[[Category: protein-ligand complex]] | [[Category: protein-ligand complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:29:54 2008'' |
Revision as of 12:29, 23 January 2008
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Crystal Structure of Estrogen Receptor alpha Complexed to a B-N Substituted Ligand
Overview
To increase the chemical diversity of bioactive molecules by incorporating, unusual elements, we have examined the replacement of a C=C double bond, with the isoelectronic, isostructural B-N bond in the context of, nonsteroidal estrogen receptor (ER) ligands. While the B-N bond was, hydrolytically labile in the unhindered cyclofenil system, the more, hindered anilino dimesitylboranes, analogs of triarylethylene estrogens, were easily prepared, hydrolytically stable, and demonstrated substantial, affinity for ERs. X-ray analysis of one ERalpha-ligand complex revealed, steric clashes with the para methyl groups distorting the receptor;, removal of these groups resulted in an increase in affinity, potency, and, transcriptional efficacy. These studies define the structural determinants, of stability and cellular bioactivity of a B-N for C=C substitution in, nonsteroidal estrogens and provide a framework for further exploration of, "elemental isomerism" for diversification of drug-like molecules.
About this Structure
2Q6J is a Protein complex structure of sequences from Homo sapiens and Mus musculus with as ligand. Full crystallographic information is available from OCA.
Reference
Elemental isomerism: a boron-nitrogen surrogate for a carbon-carbon double bond increases the chemical diversity of estrogen receptor ligands., Zhou HB, Nettles KW, Bruning JB, Kim Y, Joachimiak A, Sharma S, Carlson KE, Stossi F, Katzenellenbogen BS, Greene GL, Katzenellenbogen JA, Chem Biol. 2007 Jun;14(6):659-69. PMID:17584613
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