Kalbitzer, H. R. and Spoerner, M. and Graf, T. and König, B. (2005) A Novel Mechanism for the Modulation of the Ras-Effector Interaction by small molecules. Biochem. Biophys. Res. Commun. 334, 709 – 713.
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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.
|Institutions:|| Chemistry and Pharmacy > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Burkhard König|
Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie
|Projects:||GRK 760, Graduiertenkolleg Medizinische Chemie|
|Keywords:||Ras; 31P NMR; Anti-tumor therapy; Conformational equilibrium|
|Subjects:||500 Science > 540 Chemistry & allied sciences|
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Yes|
|Deposited On:||05 Mar 2009 10:54|
|Last Modified:||09 Nov 2010 09:57|