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| [[Image:1go9.gif|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_1go9| PDB=1go9 | SCENE= }} | | {{STRUCTURE_1go9| PDB=1go9 | SCENE= }} |
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| '''MONITORING THE STRUCTURAL CONSEQUENCES OF PHE12-->D-PHE12 AND LEU15-->AIB15 SUBSTITUTION IN H/R CORTICOTROPIN RELEASING HORMONE: IMPLICATIONS FOR DESIGN OF CRH ANTAGONISTS.'''
| | ===MONITORING THE STRUCTURAL CONSEQUENCES OF PHE12-->D-PHE12 AND LEU15-->AIB15 SUBSTITUTION IN H/R CORTICOTROPIN RELEASING HORMONE: IMPLICATIONS FOR DESIGN OF CRH ANTAGONISTS.=== |
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| ==Overview==
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| 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from the original in two positions, 12 and 15, at which the native amino acids l-phenylalanine 12 and l-leucine 15 have been replaced by the nonprotein amino acids d-phenylalanine and alpha-aminoisobutyric acid (Aib), respectively.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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_12473096}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 12473096 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_12473096}} |
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| ==About this Structure== | | ==About this Structure== |
| 1GO9 is a [[Single protein]] structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GO9 OCA]. | | 1GO9 is a [[Single protein]] structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GO9 OCA]. |
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| ==Reference== | | ==Reference== |
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| [[Category: Solutions structure]] | | [[Category: Solutions structure]] |
| [[Category: Synthetic analogue]] | | [[Category: Synthetic analogue]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 17:49:01 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 05:35:48 2008'' |
