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1go9
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(New page: 200px<br /><applet load="1go9" size="450" color="white" frame="true" align="right" spinBox="true" caption="1go9" /> '''MONITORING THE STRUCTURAL CONSEQUENCES OF PH...)
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Revision as of 23:29, 24 November 2007
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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.
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the original in two positions, 12 and 15, at which the native amino, acids l-phenylalanine 12 and l-leucine 15 have been replaced by the, nonprotein amino acids d-phenylalanine and alpha-aminoisobutyric acid, (Aib), respectively.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.
About this Structure
1GO9 is a Single protein structure of sequence from [1] with NH2 as ligand. Full crystallographic information is available from OCA.
Reference
Monitoring the structural consequences of Phe12-->D-Phe and Leu15-->Aib substitution in human/rat corticotropin releasing hormone. Implications for design of CRH antagonists., Spyroulias GA, Papazacharias S, Pairas G, Cordopatis P, Eur J Biochem. 2002 Dec;269(24):6009-19. PMID:12473096
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