A novel mechanism for the modulation of the Ras-effector interaction by small molecules.
When proteins require different conformations for their biological function, all these functional states have to coexist simultaneously in solution. However, the corresponding Gibbs free energy differences are usually rather high and thus the conformation with lowest energy predominates in solution whereas the populations of the states with higher energy (excited states) are very small. A stabilization of these excited states can be used as a novel principle to influence the activity of proteins by small molecules. For a proof of this principle, we selected the Ras protein that was shown by (31)P NMR spectroscopy to exist in solution in at least two different conformational states in its GTP form. One of these states shows a drastically reduced affinity to effectors. With Zn(2+)-cyclen we found a small molecule which selectively stabilizes the weak-binding state. It may serve as lead compound for the development of a new type of Ras-inhibitors.
Spoerner
Michael
M
Universität Regensburg, Institut für Biophysik und Physikalische Biochemie, Universitätsstrasse 31, 93053 Regensburg, Germany.
Graf
Thorsten
T
König
Burkhard
B
Kalbitzer
Hans Robert
HR
D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008970:Molecular Weight; D010761:Phosphorus Radioisotopes; D011487:Protein Conformation; D012996:Solutions; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000032:analysis* / Q000737:chemistry*
D010761:Phosphorus Radioisotopes; D012996:Solutions; D018631:ras Proteins