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New page: left|200px<br /> <applet load="2aa2" size="450" color="white" frame="true" align="right" spinBox="true" caption="2aa2, resolution 1.950Å" /> '''Mineralocorticoid ...
 
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[[Image:2aa2.gif|left|200px]]<br />
<applet load="2aa2" size="450" color="white" frame="true" align="right" spinBox="true"
caption="2aa2, resolution 1.950&Aring;" />
'''Mineralocorticoid Receptor with Bound Aldosterone'''<br />


==Overview==
==Mineralocorticoid Receptor with Bound Aldosterone==
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.
<StructureSection load='2aa2' size='340' side='right'caption='[[2aa2]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AA2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AA2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AS4:ALDOSTERONE'>AS4</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2aa2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2aa2 OCA], [https://pdbe.org/2aa2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2aa2 RCSB], [https://www.ebi.ac.uk/pdbsum/2aa2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2aa2 ProSAT]</span></td></tr>
</table>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/aa/2aa2_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2aa2 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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==
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<ref>PMID:15967794</ref>
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==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2AA2 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 BOG, SO4, AS4 and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2AA2 OCA].
</div>
<div class="pdbe-citations 2aa2" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15967794 15967794]
*[[Mineralocorticoid receptor|Mineralocorticoid receptor]]
[[Category: Homo sapiens]]
== References ==
[[Category: Single protein]]
<references/>
[[Category: Apolito, C.J.]]
__TOC__
[[Category: Bledsoe, R.K.]]
</StructureSection>
[[Category: Holt, J.A.]]
[[Category: Large Structures]]
[[Category: Lambert, M.H.]]
[[Category: Apolito CJ]]
[[Category: Madauss, K.P.]]
[[Category: Bledsoe RK]]
[[Category: Pearce, K.H.]]
[[Category: Holt JA]]
[[Category: Stanley, T.B.]]
[[Category: Lambert MH]]
[[Category: Stewart, E.L.]]
[[Category: Madauss KP]]
[[Category: Trump, R.P.]]
[[Category: Pearce KH]]
[[Category: Williams, S.P.]]
[[Category: Stanley TB]]
[[Category: Willson, T.M.]]
[[Category: Stewart EL]]
[[Category: AS4]]
[[Category: Trump RP]]
[[Category: BOG]]
[[Category: Williams SP]]
[[Category: GOL]]
[[Category: Willson TM]]
[[Category: SO4]]
[[Category: aldosterone]]
[[Category: mineralocorticoid]]
[[Category: mr]]
[[Category: nuclear receptor]]
[[Category: steroid receptor]]
 
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Latest revision as of 08:07, 4 March 2026

Mineralocorticoid Receptor with Bound Aldosterone

2aa2, resolution 1.95Å

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