2pjl
From Proteopedia
(New page: 200px<br /> <applet load="2pjl" size="450" color="white" frame="true" align="right" spinBox="true" caption="2pjl, resolution 2.300Å" /> '''Crystal Structure ...) |
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| - | [[Image:2pjl.gif|left|200px]]<br /> | + | [[Image:2pjl.gif|left|200px]]<br /><applet load="2pjl" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2pjl" size=" | + | |
caption="2pjl, resolution 2.300Å" /> | caption="2pjl, resolution 2.300Å" /> | ||
'''Crystal Structure of Human Estrogen-Related Receptor alpha in Complex with a Synthetic Inverse Agonist reveals its Novel Molecular Mechanism'''<br /> | '''Crystal Structure of Human Estrogen-Related Receptor alpha in Complex with a Synthetic Inverse Agonist reveals its Novel Molecular Mechanism'''<br /> | ||
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| + | ==Overview== | ||
| + | Inverse agonists of the constitutively active human estrogen-related, receptor alpha (ERRalpha, NR3B1) are of potential interest for several, disease indications (e.g. breast cancer, metabolic diseases, or, osteoporosis). ERRalpha is constitutively active, because its ligand, binding pocket (LBP) is practically filled with side chains (in particular, with Phe(328), which is replaced by Ala in ERRbeta and ERRgamma). We, present here the crystal structure of the ligand binding domain of, ERRalpha (containing the mutation C325S) in complex with the inverse, agonist cyclohexylmethyl-(1-p-tolyl-1H-indol-3-ylmethyl)-amine (compound, 1a), to a resolution of 2.3A(.) The structure reveals the dramatic, multiple conformational changes in the LBP, which create the necessary, space for the ligand. As a consequence of the new side chain conformation, of Phe(328) (on helix H3), Phe(510)(H12) has to move away, and thus the, activation helix H12 is displaced from its agonist position. This is a, novel mechanism of H12 inactivation, different from ERRgamma, estrogen, receptor (ER) alpha, and ERbeta. H12 binds (with a surprising binding, mode) in the coactivator groove of its ligand binding domain, at a similar, place as a coactivator peptide. This is in contrast to ERRgamma but, resembles the situation for ERalpha (raloxifene or 4-hydroxytamoxifen, complexes). Our results explain the novel molecular mechanism of an, inverse agonist for ERRalpha and provide the basis for rational drug, design to obtain isotype-specific inverse agonists of this potential new, drug target. Despite a practically filled LBP, the finding that a suitable, ligand can induce an opening of the cavity also has broad implications for, other orphan nuclear hormone receptors (e.g. the NGFI-B subfamily). | ||
==About this Structure== | ==About this Structure== | ||
| - | 2PJL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 047 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 2PJL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=047:'>047</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PJL OCA]. |
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| + | ==Reference== | ||
| + | Crystal structure of human estrogen-related receptor alpha in complex with a synthetic inverse agonist reveals its novel molecular mechanism., Kallen J, Lattmann R, Beerli R, Blechschmidt A, Blommers MJ, Geiser M, Ottl J, Schlaeppi JM, Strauss A, Fournier B, J Biol Chem. 2007 Aug 10;282(32):23231-9. Epub 2007 Jun 6. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17556356 17556356] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: nuclear hormone receptor]] | [[Category: nuclear hormone receptor]] | ||
[[Category: three-layered alpha-helical sandwich]] | [[Category: three-layered alpha-helical sandwich]] | ||
| + | [[Category: transcription]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:23:26 2008'' |
Revision as of 09:23, 23 January 2008
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Crystal Structure of Human Estrogen-Related Receptor alpha in Complex with a Synthetic Inverse Agonist reveals its Novel Molecular Mechanism
Overview
Inverse agonists of the constitutively active human estrogen-related, receptor alpha (ERRalpha, NR3B1) are of potential interest for several, disease indications (e.g. breast cancer, metabolic diseases, or, osteoporosis). ERRalpha is constitutively active, because its ligand, binding pocket (LBP) is practically filled with side chains (in particular, with Phe(328), which is replaced by Ala in ERRbeta and ERRgamma). We, present here the crystal structure of the ligand binding domain of, ERRalpha (containing the mutation C325S) in complex with the inverse, agonist cyclohexylmethyl-(1-p-tolyl-1H-indol-3-ylmethyl)-amine (compound, 1a), to a resolution of 2.3A(.) The structure reveals the dramatic, multiple conformational changes in the LBP, which create the necessary, space for the ligand. As a consequence of the new side chain conformation, of Phe(328) (on helix H3), Phe(510)(H12) has to move away, and thus the, activation helix H12 is displaced from its agonist position. This is a, novel mechanism of H12 inactivation, different from ERRgamma, estrogen, receptor (ER) alpha, and ERbeta. H12 binds (with a surprising binding, mode) in the coactivator groove of its ligand binding domain, at a similar, place as a coactivator peptide. This is in contrast to ERRgamma but, resembles the situation for ERalpha (raloxifene or 4-hydroxytamoxifen, complexes). Our results explain the novel molecular mechanism of an, inverse agonist for ERRalpha and provide the basis for rational drug, design to obtain isotype-specific inverse agonists of this potential new, drug target. Despite a practically filled LBP, the finding that a suitable, ligand can induce an opening of the cavity also has broad implications for, other orphan nuclear hormone receptors (e.g. the NGFI-B subfamily).
About this Structure
2PJL is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Crystal structure of human estrogen-related receptor alpha in complex with a synthetic inverse agonist reveals its novel molecular mechanism., Kallen J, Lattmann R, Beerli R, Blechschmidt A, Blommers MJ, Geiser M, Ottl J, Schlaeppi JM, Strauss A, Fournier B, J Biol Chem. 2007 Aug 10;282(32):23231-9. Epub 2007 Jun 6. PMID:17556356
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