Studies of the receptor-bound conformation of alphaIIbbeta3 antagonists by 15N-edited NMR spectroscopy.
We report the results of NMR studies and computer simulations of potent antagonists reflective of the alpha(IIb)beta(3) receptor-bound conformations. The peptides c[Mpa-(15)N-Arg(1)-(15)N-Gly(2)-(15)N-Asp(3)-(15)N-Phe(4)-(15)N-Arg(5)-Cys]-NH(2) (Phe-Arg analog) (Mpa: 3-mercaptopropionic acid) and c[Mpa-(15)N-Arg(1)-(15)N-Gly(2)-(15)N-Asp(3)-(15)N-Asp(4)-(15)N-Val(5)-Cys]-NH(2) (Asp-Val analog) were subjected to (15)N-edited NMR experiments to study the conformations of these peptides in the absence and in the presence of alpha(IIb)beta(3) receptor. The NMR studies of the Phe-Arg analog, a selective alpha(IIb)beta(3) antagonist, resulted in distinctly different experimental data in the presence and absence of the receptor. The computer simulations for this peptide resulted in one large family of structures consistent with the experimental data. This conformation suggests a type I beta-turn spanning residues Arg(1) and Gly(2) when bound to the receptor and we were able to establish a model for the three dimensional arrangement of the pharmacophores. The studies on the Asp-Val analog, an alpha(v)beta(3) antagonist that binds to the alpha(IIb)beta(3) with moderate affinity, resulted in conformations that are not as well defined as those for the Phe-Arg analog but are consistent with the model established for this analog. These results are important for the design of novel alpha(IIb)beta(3) antagonists.
Locardi
Elsa
E
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA.
Mattern
Ralph-Heiko
RH
Malaney
Timothy I
TI
Minasyan
Robert
R
Pierschbacher
Michael D
MD
Taulane
Joseph P
JP
Goodman
Murray
M
D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000737:chemistry; D002850:Chromatography, Gel; D003198:Computer Simulation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D009584:Nitrogen; D010446:Peptide Fragments / Q000737:chemistry; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary
D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D009584:Nitrogen