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.
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.
Flippen-Anderson
J L
JL
Laboratory for the Structure of Matter, Naval Research Laboratory, Washington DC, USA. flippen@harker.nrl.navy.mil
Deschamps
J R
JR
George
C
C
Reddy
P A
PA
Lewin
A H
AH
Brine
G A
GA
Sheldrick
G
G
Nikiforovich
G
G
D018360:Crystallography, X-Ray / Q000379:methods; D008958:Models, Molecular; D009292:Narcotic Antagonists / Q000737:chemistry*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D011487:Protein Conformation; D017450:Receptors, Opioid, mu / Q000819:agonists*; D044005:Tetrahydroisoquinolines
D009292:Narcotic Antagonists; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; C082263:tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine