1go9: Difference between revisions

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[[Image:1go9.gif|left|200px]]<br /><applet load="1go9" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

[[Image:1go9.gif|left|200px]]<br /><applet load="1go9" size="350" color="white" frame="true" align="right" spinBox="true"

caption="1go9" />

'''MONITORING THE STRUCTURAL CONSEQUENCES OF PHE12-->D-PHE12 AND LEU15-->AIB15 SUBSTITUTION IN H/R CORTICOTROPIN RELEASING HORMONE: IMPLICATIONS FOR DESIGN OF CRH ANTAGONISTS.'''<br />

==Overview==

A new human/rat CRH analogue has been synthesized using the Fmoc/tBu, solid-phase synthetic protocol. The sequence of the new peptide differs, from the original in two positions, 12 and 15, at which the native amino, acids l-phenylalanine 12 and l-leucine 15 have been replaced by the, nonprotein amino acids d-phenylalanine and alpha-aminoisobutyric acid, (Aib), respectively. The high resolution three-dimensional solution, structure of [d-Phe12, Aib15]CRH has been determined by 688 distance, constraints (656 meaningful NOE and 32 H-bonds distance limits) and 21, angle constraints. A family of 40 energy-minimized conformers was obtained, with average rmsd of 0.39 +/- 0.16 A and 0.99 +/- 0.13 A for backbone and, heavy atoms, respectively, and distance penalty functions of 0.42 +/- 0.03, A2. The NMR data acquired in a solvent system of water/trifluoroethanol, (34%/66%, v/v) revealed that this 41-polypeptide adopts an almost linear, helical structure in solution with helical content which reaches an 84% of, the residues. Structural analysis confirmed the existence of two helical, peptide fragments. The first was comprised of residues Ile6-Arg16 and the, second of residues Glu20-Ile40, forming an angle of 34.2 degrees. The, structural differences with respect to the native peptide have been, identified in the region d-Phe12-Glu20 where double substitution at, positions 12 and 15 seems to perturb the elements of the native 35-residue, helix. These structural rearrangements promote non-native intramolecular, interactions in the region of the molecule between either the hydrophobic, side-chains of d-Phe12, Aib15 and Leu18, or the charged groups of the, residue pairs Arg16-Glu20 and His13-Glu17 being responsible for changes in, hormonal functionality. This CRH analogue currently exhibits lack of any, activity.

A new human/rat CRH analogue has been synthesized using the Fmoc/tBu solid-phase synthetic protocol. The sequence of the new peptide differs from the original in two positions, 12 and 15, at which the native amino acids l-phenylalanine 12 and l-leucine 15 have been replaced by the nonprotein amino acids d-phenylalanine and alpha-aminoisobutyric acid (Aib), respectively. The high resolution three-dimensional solution structure of [d-Phe12, Aib15]CRH has been determined by 688 distance constraints (656 meaningful NOE and 32 H-bonds distance limits) and 21 angle constraints. A family of 40 energy-minimized conformers was obtained with average rmsd of 0.39 +/- 0.16 A and 0.99 +/- 0.13 A for backbone and heavy atoms, respectively, and distance penalty functions of 0.42 +/- 0.03 A2. The NMR data acquired in a solvent system of water/trifluoroethanol (34%/66%, v/v) revealed that this 41-polypeptide adopts an almost linear helical structure in solution with helical content which reaches an 84% of the residues. Structural analysis confirmed the existence of two helical peptide fragments. The first was comprised of residues Ile6-Arg16 and the second of residues Glu20-Ile40, forming an angle of 34.2 degrees. The structural differences with respect to the native peptide have been identified in the region d-Phe12-Glu20 where double substitution at positions 12 and 15 seems to perturb the elements of the native 35-residue helix. These structural rearrangements promote non-native intramolecular interactions in the region of the molecule between either the hydrophobic side-chains of d-Phe12, Aib15 and Leu18, or the charged groups of the residue pairs Arg16-Glu20 and His13-Glu17 being responsible for changes in hormonal functionality. This CRH analogue currently exhibits lack of any activity.

==About this Structure==

1GO9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] 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=1GO9 OCA].

1GO9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] 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=1GO9 OCA].

==Reference==

Line 15:

[[Category: Pairas, G.]]

[[Category: Papazacharias, S.]]

[[Category: Spyroulias, G.A.]]

[[Category: Spyroulias, G A.]]

[[Category: NH2]]

[[Category: corticotropin releasing hormone]]

Line 23:

[[Category: synthetic analogues]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Sun Nov 25 01~~:36:~~53 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:52:13 2008''

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@@ Line 1: / Line 1: @@
-[[Image:1go9.gif|left|200px]]<br /><applet load="1go9" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1go9.gif|left|200px]]<br /><applet load="1go9" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1go9" />
 '''MONITORING THE STRUCTURAL CONSEQUENCES OF PHE12-->D-PHE12 AND LEU15-->AIB15 SUBSTITUTION IN H/R CORTICOTROPIN RELEASING HORMONE: IMPLICATIONS FOR DESIGN OF CRH ANTAGONISTS.'''<br />
 ==Overview==
-A new human/rat CRH analogue has been synthesized using the Fmoc/tBu, solid-phase synthetic protocol. The sequence of the new peptide differs, from the original in two positions, 12 and 15, at which the native amino, acids l-phenylalanine 12 and l-leucine 15 have been replaced by the, nonprotein amino acids d-phenylalanine and alpha-aminoisobutyric acid, (Aib), respectively. The high resolution three-dimensional solution, structure of [d-Phe12, Aib15]CRH has been determined by 688 distance, constraints (656 meaningful NOE and 32 H-bonds distance limits) and 21, angle constraints. A family of 40 energy-minimized conformers was obtained, with average rmsd of 0.39 +/- 0.16 A and 0.99 +/- 0.13 A for backbone and, heavy atoms, respectively, and distance penalty functions of 0.42 +/- 0.03, A2. The NMR data acquired in a solvent system of water/trifluoroethanol, (34%/66%, v/v) revealed that this 41-polypeptide adopts an almost linear, helical structure in solution with helical content which reaches an 84% of, the residues. Structural analysis confirmed the existence of two helical, peptide fragments. The first was comprised of residues Ile6-Arg16 and the, second of residues Glu20-Ile40, forming an angle of 34.2 degrees. The, structural differences with respect to the native peptide have been, identified in the region d-Phe12-Glu20 where double substitution at, positions 12 and 15 seems to perturb the elements of the native 35-residue, helix. These structural rearrangements promote non-native intramolecular, interactions in the region of the molecule between either the hydrophobic, side-chains of d-Phe12, Aib15 and Leu18, or the charged groups of the, residue pairs Arg16-Glu20 and His13-Glu17 being responsible for changes in, hormonal functionality. This CRH analogue currently exhibits lack of any, activity.
+A new human/rat CRH analogue has been synthesized using the Fmoc/tBu solid-phase synthetic protocol. The sequence of the new peptide differs from the original in two positions, 12 and 15, at which the native amino acids l-phenylalanine 12 and l-leucine 15 have been replaced by the nonprotein amino acids d-phenylalanine and alpha-aminoisobutyric acid (Aib), respectively. The high resolution three-dimensional solution structure of [d-Phe12, Aib15]CRH has been determined by 688 distance constraints (656 meaningful NOE and 32 H-bonds distance limits) and 21 angle constraints. A family of 40 energy-minimized conformers was obtained with average rmsd of 0.39 +/- 0.16 A and 0.99 +/- 0.13 A for backbone and heavy atoms, respectively, and distance penalty functions of 0.42 +/- 0.03 A2. The NMR data acquired in a solvent system of water/trifluoroethanol (34%/66%, v/v) revealed that this 41-polypeptide adopts an almost linear helical structure in solution with helical content which reaches an 84% of the residues. Structural analysis confirmed the existence of two helical peptide fragments. The first was comprised of residues Ile6-Arg16 and the second of residues Glu20-Ile40, forming an angle of 34.2 degrees. The structural differences with respect to the native peptide have been identified in the region d-Phe12-Glu20 where double substitution at positions 12 and 15 seems to perturb the elements of the native 35-residue helix. These structural rearrangements promote non-native intramolecular interactions in the region of the molecule between either the hydrophobic side-chains of d-Phe12, Aib15 and Leu18, or the charged groups of the residue pairs Arg16-Glu20 and His13-Glu17 being responsible for changes in hormonal functionality. This CRH analogue currently exhibits lack of any activity.
 ==About this Structure==
-GO9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] 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=1GO9 OCA].
+GO9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] 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=1GO9 OCA].
 ==Reference==
@@ Line 15: / Line 15: @@
 [[Category: Pairas, G.]]
 [[Category: Papazacharias, S.]]
-[[Category: Spyroulias, G.A.]]
+[[Category: Spyroulias, G A.]]
 [[Category: NH2]]
 [[Category: corticotropin releasing hormone]]
@@ Line 23: / Line 23: @@
 [[Category: synthetic analogues]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 25 01:36:53 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:52:13 2008''