Sidechain and backbone requirements for anti-invasive activity of laminin peptide 11
| Autor: | Sheng Dai, Jean R. Starkey, Edward A. Dratz |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Models Molecular Lung Neoplasms Magnetic Resonance Spectroscopy Molecular model Stereochemistry Melanoma Experimental Biophysics Peptide Sequence (biology) Laminin peptide 11 Biochemistry Basement Membrane Mice Molecular dynamics Structural Biology Tumor Cells Cultured Animals Neoplasm Invasiveness Molecular Biology Alanine chemistry.chemical_classification Mice Inbred BALB C Cyclic peptide Peptide Conformation chemistry Drug Design Thermodynamics Female Laminin Oligopeptides |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1429:187-207 |
| ISSN: | 0167-4838 |
| Popis: | The structure of laminin peptide 11 (CDPGYIGSR-NH2) contains valuable information for the design of mimetic compounds with anti-invasive and anti-metastatic properties. An alanine scan replacement experiment identified Tyr5, Ile6 and Arg9 residues as contributing significantly to anti-invasive activity. Circular dichroism spectra and NMR αH chemical shift values both supported the existence of populations of nonrandom coil solution structures for the analogs tested. A d -Ala4 for Gly4 substituted analog completely lost activity, while an l -Ala4 for Gly4 substituted analog retained half the activity of the parent peptide. These results complement our previous findings with d/l alanine substitutions at the Gly7 position, and together they suggest an ‘S’-shaped backbone as likely for the active peptide conformation. NMR-constrained molecular modeling supported a direct involvement of the Tyr5 and Ile6 sidechains in conferring bioactivity, and indicated that the Tyr5 sidechain was buried in the Ala2 for Asp2 substitution. Based on the fact that the peptide 11 sequence derives from the disulfide bonded c-loop of an LE-repeat, we synthesized the cyclic CDPGYIGSRC -NH2 peptide. This analog exhibited good anti-invasive and anti-metastatic activity. NMR modeling experiments suggested that the trans-proline cyclic peptide, would favor an ‘S’-shaped backbone conformation. Full retro-inverso analogs of peptide 11 were shown to have anti-invasive activity inferior to that of peptide 11. This weak bioactivity was probed using NMR-constrained molecular dynamics, and revealed potential conformations which limited the ability of the required sidechains to mimic the positions of those in the native peptide conformations. |
| Databáze: | OpenAIRE |
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