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New page: left|200px<br /><applet load="2o8z" size="350" color="white" frame="true" align="right" spinBox="true" caption="2o8z" /> '''Bound Structure of CRF1 Extracellular Domain...
 
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[[Image:2o8z.gif|left|200px]]<br /><applet load="2o8z" size="350" color="white" frame="true" align="right" spinBox="true"
caption="2o8z" />
'''Bound Structure of CRF1 Extracellular Domain Antagonist'''<br />


==Overview==
==Bound Structure of CRF1 Extracellular Domain Antagonist==
Natural peptide agonists of corticotrophin-releasing factor (CRF), receptors bind to the receptor by a two-site mechanism as follows: the, carboxyl end of the ligand binds the N-terminal extracellular domain (ECD), of the receptor and the amino portion of the ligand binds the, extracellular face of the seven transmembrane region. Recently, peptide, antagonists homologous to the 12 C-terminal residues of CRF have been, derived, which bind the CRF(1) receptor through an interaction with the, ECD. Here we characterized the binding of a minimal 12-residue peptide, antagonist while bound to the isolated ECD of the CRF(1) receptor. We have, expressed and purified soluble and properly folded ECD independent from, the seven-transmembrane region as a thioredoxin fusion protein in, Escherichia coli. A model of the peptide antagonist, cyclic, corticotrophin-releasing factor residues 30-41 (cCRF(30-41)), was, calculated while bound to the recombinant ECD using transferred nuclear, Overhauser effect spectroscopy. Although the peptide is unstructured in, solution, it adopts an alpha-helical conformation when bound to the ECD., Residues of cCRF(30-41) comprising the binding interface with the ECD were, mapped using saturation transfer difference NMR. Two hydrophobic residues, (Met(38) and Ile(41)) as well as two amide groups (Asn(34) and the, C-terminal amide) on one face of the helix defined the binding epitope of, the antagonist. This epitope may be used as a starting point for, development of non-peptide antagonists targeting the ECD of this receptor.
<StructureSection load='2o8z' size='340' side='right'caption='[[2o8z]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2o8z]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2O8Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2O8Z FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=2o8z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2o8z OCA], [https://pdbe.org/2o8z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2o8z RCSB], [https://www.ebi.ac.uk/pdbsum/2o8z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2o8z ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Natural peptide agonists of corticotrophin-releasing factor (CRF) receptors bind to the receptor by a two-site mechanism as follows: the carboxyl end of the ligand binds the N-terminal extracellular domain (ECD) of the receptor and the amino portion of the ligand binds the extracellular face of the seven transmembrane region. Recently, peptide antagonists homologous to the 12 C-terminal residues of CRF have been derived, which bind the CRF(1) receptor through an interaction with the ECD. Here we characterized the binding of a minimal 12-residue peptide antagonist while bound to the isolated ECD of the CRF(1) receptor. We have expressed and purified soluble and properly folded ECD independent from the seven-transmembrane region as a thioredoxin fusion protein in Escherichia coli. A model of the peptide antagonist, cyclic corticotrophin-releasing factor residues 30-41 (cCRF(30-41)), was calculated while bound to the recombinant ECD using transferred nuclear Overhauser effect spectroscopy. Although the peptide is unstructured in solution, it adopts an alpha-helical conformation when bound to the ECD. Residues of cCRF(30-41) comprising the binding interface with the ECD were mapped using saturation transfer difference NMR. Two hydrophobic residues (Met(38) and Ile(41)) as well as two amide groups (Asn(34) and the C-terminal amide) on one face of the helix defined the binding epitope of the antagonist. This epitope may be used as a starting point for development of non-peptide antagonists targeting the ECD of this receptor.


==About this Structure==
NMR structural characterization of a minimal peptide antagonist bound to the extracellular domain of the corticotropin-releasing factor1 receptor.,Mesleh MF, Shirley WA, Heise CE, Ling N, Maki RA, Laura RP J Biol Chem. 2007 Mar 2;282(9):6338-46. Epub 2006 Dec 27. PMID:17192263<ref>PMID:17192263</ref>
2O8Z is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=ACE:'>ACE</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2O8Z OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
NMR structural characterization of a minimal peptide antagonist bound to the extracellular domain of the corticotropin-releasing factor1 receptor., Mesleh MF, Shirley WA, Heise CE, Ling N, Maki RA, Laura RP, J Biol Chem. 2007 Mar 2;282(9):6338-46. Epub 2006 Dec 27. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17192263 17192263]
</div>
[[Category: Protein complex]]
<div class="pdbe-citations 2o8z" style="background-color:#fffaf0;"></div>
[[Category: Heise, C.E.]]
== References ==
[[Category: Laura, R.P.]]
<references/>
[[Category: Ling, N.]]
__TOC__
[[Category: Maki, R.A.]]
</StructureSection>
[[Category: Mesleh, M.F.]]
[[Category: Homo sapiens]]
[[Category: Shirley, W.A.]]
[[Category: Large Structures]]
[[Category: ACE]]
[[Category: Heise CE]]
[[Category: crf]]
[[Category: Laura RP]]
[[Category: ecd]]
[[Category: Ling N]]
[[Category: extracellular domain]]
[[Category: Maki RA]]
[[Category: gpcr]]
[[Category: Mesleh MF]]
[[Category: helical]]
[[Category: Shirley WA]]
[[Category: peptide ligand]]
 
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