2oax: Difference between revisions
New page: left|200px<br /> <applet load="2oax" size="450" color="white" frame="true" align="right" spinBox="true" caption="2oax, resolution 2.29Å" /> '''Crystal structure o... |
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'''Crystal structure of the S810L mutant mineralocorticoid receptor associated with SC9420'''<br /> | '''Crystal structure of the S810L mutant mineralocorticoid receptor associated with SC9420'''<br /> | ||
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==Overview== | ==Overview== | ||
Spirolactones are potent antagonists of the mineralocorticoid receptor, (MR), a ligand-induced transcription factor belonging to the nuclear, receptor superfamily. Spirolactones are synthetic molecules characterized, by having a C17 gamma-lactone, which is responsible for their antagonist, character. They harbor various substituents at several positions of the, steroid skeleton that modulate their potency in ways that remain to be, determined. This is particularly obvious for C7 substituents. The, instability of antagonist-MR complexes makes them difficult to, crystallize. We took advantage of the S810L activating mutation in MR, (MRS810L), which increases the stability of ligand-MR complexes, to, crystallize the ligand-binding domain (LBD) of MRS810L associated with, SC9420, a spirolactone with a C7 thioacetyl group. The crystal structure, makes it possible to identify the contacts between SC9420 and MR, and, elucidate the role of Met852 in the mode of accommodation of the C7, substituent of SC9420. The transactivation activities of MRS810L/Q776A, MRS810L/R817A and MRS810L/N770A reveal that the contacts between SC9420, and the Gln776 and Arg817 residues are crucial to maintaining MRS810L in, its active state, whereas the contact between SC9420 and the Asn770, residue only contributes to the high affinity of SC9420 for MR. Moreover, docking experiments with other C7-substituted spirolactones revealed that, the MRS810L-activating potency of spirolactones is linked to the ability, of their C7 substituent to be accommodated in LBD. Remarkably, the, MRS810L-activating and MRWT-inactivating potencies of the C7-substituted, spirolactones follow the same order, suggesting that the C7 substituent is, accommodated in the same way in MRS810L and MRWT. Thus, the MRS810L, structure may provide a powerful tool for designing new, more effective, MR antagonists. | Spirolactones are potent antagonists of the mineralocorticoid receptor, (MR), a ligand-induced transcription factor belonging to the nuclear, receptor superfamily. Spirolactones are synthetic molecules characterized, by having a C17 gamma-lactone, which is responsible for their antagonist, character. They harbor various substituents at several positions of the, steroid skeleton that modulate their potency in ways that remain to be, determined. This is particularly obvious for C7 substituents. The, instability of antagonist-MR complexes makes them difficult to, crystallize. We took advantage of the S810L activating mutation in MR, (MRS810L), which increases the stability of ligand-MR complexes, to, crystallize the ligand-binding domain (LBD) of MRS810L associated with, SC9420, a spirolactone with a C7 thioacetyl group. The crystal structure, makes it possible to identify the contacts between SC9420 and MR, and, elucidate the role of Met852 in the mode of accommodation of the C7, substituent of SC9420. The transactivation activities of MRS810L/Q776A, MRS810L/R817A and MRS810L/N770A reveal that the contacts between SC9420, and the Gln776 and Arg817 residues are crucial to maintaining MRS810L in, its active state, whereas the contact between SC9420 and the Asn770, residue only contributes to the high affinity of SC9420 for MR. Moreover, docking experiments with other C7-substituted spirolactones revealed that, the MRS810L-activating potency of spirolactones is linked to the ability, of their C7 substituent to be accommodated in LBD. Remarkably, the, MRS810L-activating and MRWT-inactivating potencies of the C7-substituted, spirolactones follow the same order, suggesting that the C7 substituent is, accommodated in the same way in MRS810L and MRWT. Thus, the MRS810L, structure may provide a powerful tool for designing new, more effective, MR antagonists. | ||
==About this Structure== | ==About this Structure== | ||
2OAX 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 SNL as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 2OAX 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=SNL:'>SNL</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OAX OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: hypertension; antagonist; spironolactone]] | [[Category: hypertension; antagonist; spironolactone]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:03:10 2008'' | ||
Revision as of 13:03, 23 January 2008
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Crystal structure of the S810L mutant mineralocorticoid receptor associated with SC9420
OverviewOverview
Spirolactones are potent antagonists of the mineralocorticoid receptor, (MR), a ligand-induced transcription factor belonging to the nuclear, receptor superfamily. Spirolactones are synthetic molecules characterized, by having a C17 gamma-lactone, which is responsible for their antagonist, character. They harbor various substituents at several positions of the, steroid skeleton that modulate their potency in ways that remain to be, determined. This is particularly obvious for C7 substituents. The, instability of antagonist-MR complexes makes them difficult to, crystallize. We took advantage of the S810L activating mutation in MR, (MRS810L), which increases the stability of ligand-MR complexes, to, crystallize the ligand-binding domain (LBD) of MRS810L associated with, SC9420, a spirolactone with a C7 thioacetyl group. The crystal structure, makes it possible to identify the contacts between SC9420 and MR, and, elucidate the role of Met852 in the mode of accommodation of the C7, substituent of SC9420. The transactivation activities of MRS810L/Q776A, MRS810L/R817A and MRS810L/N770A reveal that the contacts between SC9420, and the Gln776 and Arg817 residues are crucial to maintaining MRS810L in, its active state, whereas the contact between SC9420 and the Asn770, residue only contributes to the high affinity of SC9420 for MR. Moreover, docking experiments with other C7-substituted spirolactones revealed that, the MRS810L-activating potency of spirolactones is linked to the ability, of their C7 substituent to be accommodated in LBD. Remarkably, the, MRS810L-activating and MRWT-inactivating potencies of the C7-substituted, spirolactones follow the same order, suggesting that the C7 substituent is, accommodated in the same way in MRS810L and MRWT. Thus, the MRS810L, structure may provide a powerful tool for designing new, more effective, MR antagonists.
About this StructureAbout this Structure
2OAX is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Structural Basis of Spirolactone Recognition by the Mineralocorticoid Receptor., Huyet J, Pinon GM, Fay MR, Fagart J, Rafestin-Oblin ME, Mol Pharmacol. 2007 Jun 14;. PMID:17569793
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