1ru5: Difference between revisions

Revision as of 15:54, 21 February 2008

Solution structure of porcine peptide YY (pPYY)

OverviewOverview

Here, we investigate the structure of porcine peptide YY (pPYY) both when unligated in solution at pH 4.2 and when bound to dodecylphosphocholine (DPC) micelles at pH 5.5. pPYY in solution displays the PP-fold, with the N-terminal segment being back-folded onto the C-terminal alpha-helix, which extends from residue 17 to 31. In contrast to the solution structure of Keire et al. published in the year 2000 the C-terminal helix does not display a kink around residue 23-25. The root mean square deviation (RMSD) for backbone atoms of the NMR ensemble of conformers to the mean structure is 0.99(+/-0.35) Angstrom for residues 14-31. The back-fold is supported by values of 0.60+/-0.1 for the (15)N(1)H-NOE and by generalized order parameters S(2) of 0.74+/-0.1 for residues 5-31 which indicate that the peptide is folded in that segment. We have additionally used DPC micelles as a membrane model and determined the structure of pPYY when bound to it. Therein, an alpha-helix occurs in the segment comprising residues 17-31 and the N terminus freely diffuses in solution. The hydrophobic side of the amphipathic helix forms the micelle-binding interface and hydrophobic side-chains extend into the micelle interior. A significant stabilization of helical conformation occurs in the C-terminal pentapeptide, which is important for receptor binding. The latter is supported by positive values of the heteronuclear NOE in that segment (0.52+/-0.1 compared to 0.08+/-0.4 for the unligated form) and by values of S(2) of 0.6+/-0.2 (versus 0.38+/-0.2 for the unligated form). The structures of micelle-bound pPYY and pNPY are much more similar than those of pPYY and bPP with pairwise RMSDs of 1.23(+/-0.21)A or 3.21(+/-0.39) Angstrom, respectively. In contrast to the conformational similarities in the DPC-bound state their structures in solution are very different. In fact pPYY is more similar to bPP, which with its strong preference for the Y(4) receptor displays a completely different binding profile. Considering the high degree of sequence homology of pNPY and pPYY (>80%) and the fact, that their binding affinities at all receptor subtypes are high and, more importantly, rather similar, it is much more likely that PYY and NPY are recognized by the Y receptors from the membrane-bound state. As a consequence of the latter the PP-fold is not important for recognition of PYY or NPY at the Y receptors. To our knowledge this work provides for the first time strong arguments derived from structural data that support a membrane-bound receptor recognition pathway.

About this StructureAbout this Structure

1RU5 is a Single protein structure of sequence from Sus scrofa with as ligand. Full crystallographic information is available from OCA.

ReferenceReference

Structural similarities of micelle-bound peptide YY (PYY) and neuropeptide Y (NPY) are related to their affinity profiles at the Y receptors., Lerch M, Mayrhofer M, Zerbe O, J Mol Biol. 2004 Jun 18;339(5):1153-68. PMID:15178255

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-[[Image:1ru5.jpg|left|200px]]<br /><applet load="1ru5" size="450" color="white" frame="true" align="right" spinBox="true"
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 caption="1ru5" />
 '''Solution structure of porcine peptide YY (pPYY)'''<br />
 ==Overview==
-Here, we investigate the structure of porcine peptide YY (pPYY) both when, unligated in solution at pH 4.2 and when bound to dodecylphosphocholine, (DPC) micelles at pH 5.5. pPYY in solution displays the PP-fold, with the, N-terminal segment being back-folded onto the C-terminal alpha-helix, which extends from residue 17 to 31. In contrast to the solution structure, of Keire et al. published in the year 2000 the C-terminal helix does not, display a kink around residue 23-25. The root mean square deviation (RMSD), for backbone atoms of the NMR ensemble of conformers to the mean structure, is 0.99(+/-0.35) Angstrom for residues 14-31. The back-fold is supported, by values of 0.60+/-0.1 for the (15)N(1)H-NOE and by generalized order, parameters S(2) of 0.74+/-0.1 for residues 5-31 which indicate that the, peptide is folded in that segment. We have additionally used DPC micelles, as a membrane model and determined the structure of pPYY when bound to it., Therein, an alpha-helix occurs in the segment comprising residues 17-31, and the N terminus freely diffuses in solution. The hydrophobic side of, the amphipathic helix forms the micelle-binding interface and hydrophobic, side-chains extend into the micelle interior. A significant stabilization, of helical conformation occurs in the C-terminal pentapeptide, which is, important for receptor binding. The latter is supported by positive values, of the heteronuclear NOE in that segment (0.52+/-0.1 compared to, 0.08+/-0.4 for the unligated form) and by values of S(2) of 0.6+/-0.2, (versus 0.38+/-0.2 for the unligated form). The structures of, micelle-bound pPYY and pNPY are much more similar than those of pPYY and, bPP with pairwise RMSDs of 1.23(+/-0.21)A or 3.21(+/-0.39) Angstrom, respectively. In contrast to the conformational similarities in the, DPC-bound state their structures in solution are very different. In fact, pPYY is more similar to bPP, which with its strong preference for the Y(4), receptor displays a completely different binding profile. Considering the, high degree of sequence homology of pNPY and pPYY (&gt;80%) and the fact, that their binding affinities at all receptor subtypes are high and, more, importantly, rather similar, it is much more likely that PYY and NPY are, recognized by the Y receptors from the membrane-bound state. As a, consequence of the latter the PP-fold is not important for recognition of, PYY or NPY at the Y receptors. To our knowledge this work provides for the, first time strong arguments derived from structural data that support a, membrane-bound receptor recognition pathway.
+Here, we investigate the structure of porcine peptide YY (pPYY) both when unligated in solution at pH 4.2 and when bound to dodecylphosphocholine (DPC) micelles at pH 5.5. pPYY in solution displays the PP-fold, with the N-terminal segment being back-folded onto the C-terminal alpha-helix, which extends from residue 17 to 31. In contrast to the solution structure of Keire et al. published in the year 2000 the C-terminal helix does not display a kink around residue 23-25. The root mean square deviation (RMSD) for backbone atoms of the NMR ensemble of conformers to the mean structure is 0.99(+/-0.35) Angstrom for residues 14-31. The back-fold is supported by values of 0.60+/-0.1 for the (15)N(1)H-NOE and by generalized order parameters S(2) of 0.74+/-0.1 for residues 5-31 which indicate that the peptide is folded in that segment. We have additionally used DPC micelles as a membrane model and determined the structure of pPYY when bound to it. Therein, an alpha-helix occurs in the segment comprising residues 17-31 and the N terminus freely diffuses in solution. The hydrophobic side of the amphipathic helix forms the micelle-binding interface and hydrophobic side-chains extend into the micelle interior. A significant stabilization of helical conformation occurs in the C-terminal pentapeptide, which is important for receptor binding. The latter is supported by positive values of the heteronuclear NOE in that segment (0.52+/-0.1 compared to 0.08+/-0.4 for the unligated form) and by values of S(2) of 0.6+/-0.2 (versus 0.38+/-0.2 for the unligated form). The structures of micelle-bound pPYY and pNPY are much more similar than those of pPYY and bPP with pairwise RMSDs of 1.23(+/-0.21)A or 3.21(+/-0.39) Angstrom, respectively. In contrast to the conformational similarities in the DPC-bound state their structures in solution are very different. In fact pPYY is more similar to bPP, which with its strong preference for the Y(4) receptor displays a completely different binding profile. Considering the high degree of sequence homology of pNPY and pPYY (&gt;80%) and the fact, that their binding affinities at all receptor subtypes are high and, more importantly, rather similar, it is much more likely that PYY and NPY are recognized by the Y receptors from the membrane-bound state. As a consequence of the latter the PP-fold is not important for recognition of PYY or NPY at the Y receptors. To our knowledge this work provides for the first time strong arguments derived from structural data that support a membrane-bound receptor recognition pathway.
 ==About this Structure==
-RU5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with NH2 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1RU5 OCA].
+RU5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with <scene name='pdbligand=NH2:'>NH2</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RU5 OCA].
 ==Reference==
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 [[Category: pp-fold]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 01:52:16 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:54:36 2008''