X-ray structure of Tyr-D-Tic-Phe-Phe-NH2 (D-TIPP-NH2), a highly potent mu-receptor selective opioid agonist. Comparison with proposed model structures.

Abstract

Tyr-D-Tic-Phe-Phe-NH2 (D-TIPP), a linear tetrapeptide containing the conformationally restricted Tic residue (tetrahydroisoquinoline-3-carboxylic acid), is an opioid agonist which exhibits high affinity and selectivity for the mu-receptor. Its conformational features have been studied using a combination, a solid-state (X-ray) and modeling (molecular mechanics and Monte Carlo simulations) methods. The results of the X-ray study showed two distinct conformers for D-TIPP, with the main differences lying in the orientation of the Tyr side-chain and the presence of both D-Tic(+) and D-Tic(-) conformations for the D-Tic residue. The peptide backbone is folded and stabilized by the formation of one intramolecular hydrogen bond. The modeling results also indicated a folded backbone for the peptide and both cis and trans conformers for the D-Tic residue are found in the lowest-energy structures. Comparison of the X-ray and modeling results shows many similarities especially around the D-Tic residue.

• Authors: J L Flippen-Anderson, J R Deschamps, C George, P A Reddy, A H Lewin, G A Brine, G Sheldrick, G Nikiforovich
• Journal: The journal of peptide research : official journal of the American Peptide Society (J Pept Res) Vol. 49 Issue 5 Pg. 384-93 (May 1997) ISSN: 1397-002X [Print] Denmark
• PMID: 9211219 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Narcotic Antagonists
• Oligopeptides
• Receptors, Opioid, mu
• Tetrahydroisoquinolines
• tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine

Topics

• Crystallography, X-Ray (methods)
• Models, Molecular
• Narcotic Antagonists (chemistry)
• Oligopeptides (chemical synthesis, chemistry)
• Protein Conformation
• Receptors, Opioid, mu (agonists)
• Tetrahydroisoquinolines