2aa5
From Proteopedia
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|ACTIVITY= | |ACTIVITY= | ||
|GENE= NR3C2, MCR, MLR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= NR3C2, MCR, MLR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2aa2|2AA2]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2aa5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2aa5 OCA], [http://www.ebi.ac.uk/pdbsum/2aa5 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2aa5 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Ligand binding is the first step in hormone regulation of mineralocorticoid receptor (MR) activity. Here, we report multiple crystal structures of MR (NR3C2) bound to both agonist and antagonists. These structures combined with mutagenesis studies reveal that maximal receptor activation involves an intricate ligand-mediated hydrogen bond network with Asn770 which serves dual roles: stabilization of the loop preceding the C-terminal activation function-2 helix and direct contact with the hormone ligand. In addition, most activating ligands hydrogen bond to Thr945 on helix 10. Structural characterization of the naturally occurring S810L mutant explains how stabilization of a helix 3/helix 5 interaction can circumvent the requirement for this hydrogen bond network. Taken together, these results explain the potency of MR activation by aldosterone, the weak activation induced by progesterone and the antihypertensive agent spironolactone, and the binding selectivity of cortisol over cortisone. | Ligand binding is the first step in hormone regulation of mineralocorticoid receptor (MR) activity. Here, we report multiple crystal structures of MR (NR3C2) bound to both agonist and antagonists. These structures combined with mutagenesis studies reveal that maximal receptor activation involves an intricate ligand-mediated hydrogen bond network with Asn770 which serves dual roles: stabilization of the loop preceding the C-terminal activation function-2 helix and direct contact with the hormone ligand. In addition, most activating ligands hydrogen bond to Thr945 on helix 10. Structural characterization of the naturally occurring S810L mutant explains how stabilization of a helix 3/helix 5 interaction can circumvent the requirement for this hydrogen bond network. Taken together, these results explain the potency of MR activation by aldosterone, the weak activation induced by progesterone and the antihypertensive agent spironolactone, and the binding selectivity of cortisol over cortisone. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600983 600983]], Pseudohypoaldosteronism type I, autosomal dominant OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600983 600983]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Williams, S P.]] | [[Category: Williams, S P.]] | ||
[[Category: Willson, T M.]] | [[Category: Willson, T M.]] | ||
| - | [[Category: STR]] | ||
[[Category: mineralocorticoid receptor]] | [[Category: mineralocorticoid receptor]] | ||
[[Category: mr]] | [[Category: mr]] | ||
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[[Category: steroid receptor]] | [[Category: steroid receptor]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:49:55 2008'' |
Revision as of 22:49, 30 March 2008
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| , resolution 2.200Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Gene: | NR3C2, MCR, MLR (Homo sapiens) | ||||||
| Related: | 2AA2
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Mineralocorticoid Receptor with Bound Progesterone
Overview
Ligand binding is the first step in hormone regulation of mineralocorticoid receptor (MR) activity. Here, we report multiple crystal structures of MR (NR3C2) bound to both agonist and antagonists. These structures combined with mutagenesis studies reveal that maximal receptor activation involves an intricate ligand-mediated hydrogen bond network with Asn770 which serves dual roles: stabilization of the loop preceding the C-terminal activation function-2 helix and direct contact with the hormone ligand. In addition, most activating ligands hydrogen bond to Thr945 on helix 10. Structural characterization of the naturally occurring S810L mutant explains how stabilization of a helix 3/helix 5 interaction can circumvent the requirement for this hydrogen bond network. Taken together, these results explain the potency of MR activation by aldosterone, the weak activation induced by progesterone and the antihypertensive agent spironolactone, and the binding selectivity of cortisol over cortisone.
About this Structure
2AA5 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor., Bledsoe RK, Madauss KP, Holt JA, Apolito CJ, Lambert MH, Pearce KH, Stanley TB, Stewart EL, Trump RP, Willson TM, Williams SP, J Biol Chem. 2005 Sep 2;280(35):31283-93. Epub 2005 Jun 20. PMID:15967794
Page seeded by OCA on Mon Mar 31 01:49:55 2008
