Micelle-bound conformational preferences of a peptide derived from a murine major histocompatibility complex class I molecule.
Models of the micelle-bound conformation of a 17-residue major histocompatibility complex-derived peptide, [Ala85]Dk(69-85), have been determined by NMR spectroscopy and simulated annealing calculations. This peptide is a truncated, substituted version of Dk(61-85), which is a fragment of the murine major histocompatibility complex class I molecule H-2Dk. Dk(61-85) has been shown to adopt an ordered conformation required for augmentation of insulin-stimulated glucose uptake (Stagsted, J., Baase, W. A., Goldstein, A., and Olsson, L. (1991) J. Biol. Chem. 266, 12844-12847). [Ala85]Dk(69-85) retains full biological activity. Thirty-eight converged NMR structures of [Ala85]Dk(69-85) bound to dodecyl phosphocholine micelles have been generated. The NMR-derived models display a propensity for a type-I beta-bend involving residues 73-76 and an amphipathic helical region involving residues 77-84. CD spectra yield a helical content (8% at 20-25 degrees C) consistent with transient, partial helix formation. The relative orientation of the beta-bend region with respect to the helical region is not well defined by the NMR data. This may reflect true heterogeneity of the micelle-bound conformation. The NMR structures were compared with a model of [Ala85]Dk(69-85) derived from the x-ray coordinates of the human major histocompatibility complex class I allele HLA-Aw68 (Garrett, T. P. J., Saper, M. A., Bjorkmann, P. J., Strominger, T. L., and Wiley, D. C. (1989) Nature 342, 692-696). Structural features that are important for the bioactivity of [Ala85]Dk(69-85) are discussed with reference to reported structure-activity relationships (Stagsted, J., Mapelli, C., Myers, C., Matthews, B. W., Anfinsen, C. B., Goldstein, A., and Olsson, L. (1993) Proc. Natl. Acad. Sci. U.S.A., in press). A general description of the structural properties of the putative receptor site(s) that are likely to be required for binding [Ala85]Dk(69-85) is given.
Constantine
K L
KL
Department of Macromolecular Nuclear Magnetic Resonance, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543.
Mapelli
C
C
Meyers
C A
CA
Friedrichs
M S
MS
Krystek
S
S
Mueller
L
L
D000595:Amino Acid Sequence; D000818:Animals; D002942:Circular Dichroism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008285:Major Histocompatibility Complex; D051379:Mice; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation
D015395:Histocompatibility Antigens Class I; D008823:Micelles; D010446:Peptide Fragments