Author: Snow, Mark E. ; Wang, Yu-Sen ; Heimark, Larry ; Kirschmeier, Paul ; Ganguly, Ashit K. ; Huang, Eric C. ; Girijavallabhan, Viyyoor M. ; DeLisle, Dorothy M. ; Kissinger, Charles R. ; Love, Robert A. ; Sisson, Wess A. ; Taveras, Arthur G. ; Tsarbopoulos, Anthony ; Doll, Ronald J. ; Villafranca, J. Ernest ; Webber, Steve E. ; Brown, Joan E. ; Vibulbhan, Bancha ; Brown, Edward L. ; Cesarz, David ; Aust, Robert M. ; Remiszewski, Stacy ; Fuhrman, Shella A. ; del Rosario, J. ; Pramanik, Birendra N. ; Hendrickson, Thomas F.

Mutated, tumorigenic Ras is present in a variety of human tumors. Compounds that inhibit tumorigenic Ras function may be useful in the treatment of Ras-related tumors. The interaction of a novel GDP exchange inhibitor (SCH-54292) with the Ras-GDP protein was studied by NMR spectroscopy. The binding of the inhibitor to the Ras protein was enhanced at low Mg2+ concentrations, which enabled the preparation of a stable complex for NMR study. To understand the enhanced inhibitor binding and the increased GDP dissociation rates of the Ras protein, the conformational changes of the Ras protein at low Mg2+ concentrations was investigated using two-dimensional 1H-15N HSQC experiments. The Ras protein existed in two conformations in slow exchange on the NMR time scale under such conditions. The conformational changes mainly occurred in the GDP binding pocket, in the switch I and the switch II regions, and were reversible. The Ras protein resumed its regular conformation after an excess amount of Mg2+ was added. A model of the inhibitor in complex with the Ras-GDP protein was derived from intra- and intermolecular NOE distance constraints, and revealed that the inhibitor bound to the critical switch II region of the Ras protein.

01 Oct 1998·Journal of Mass SpectrometryQ4 · CHEMISTRY

Electrospray ionization mass spectrometry for the study of non-covalent complexes: an emerging technology

Q4 · CHEMISTRY

Article

Author: Ashit K. Ganguly ; Urooj A. Mirza ; Peter L. Bartner ; Yan-Hui Liu ; Birendra N. Pramanik

The detection of non-covalent complexes in the mass range 19,000-34,000 Da, using electrospray ionization mass spectrometry (ESI-MS), is reviewed. The examples discussed include (1) a protein-ligand interaction (ras-GDP), (2) an inhibitor-protein-ligand interaction (SCH 54292/SCH 54341-ras-GDP), (3) a protein-protein interaction (gamma-IFN homodimer) and (4) a protein-metal complex [HCV (1-181)-Zn]. In each case, the ESI-MS method is capable of releasing the intact non-covalent complex from its native solution state into the gas phase in the form of multiply-charge ions. The molecular masses of these complexes were determined with a mass accuracy of better than 0.01%, which is far superior to the traditional methods of sodium dodecyl sulfate polyacrylamide gel electrophoresis and gel permeation chromatography. The method provides the researcher with a quick, reliable and reproducible method for probing difficult biological problems. The key to success in the study of non-covalent complexes depends on careful understanding and manipulation of ESI source parameters and sample solution conditions; special care must be taken with the source orifice potential and the solution pH and organic co-solvents must be avoided. This paper also illustrates the usefulness of ESI-MS for addressing biological problems leading to the discovery of new therapeutics; the approach involves the rapid screening of potential drug candidates, such as weakly bound inhibitors.

01 May 1997·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Detection and structural characterization of ras oncoprotein-inhibitors complexes by electrospray mass spectrometry

Q3 · MEDICINE

Article

Author: M.E. Snow ; S. Remiszewski ; E.C. Huang ; J.E. Brown ; R.J. Doll ; A.K. Ganguly ; B.N. Pramanik ; L. Heimark ; Y.S. Wang ; A.G. Taveras ; S. Liberles ; B. Vibulbhan ; J. del Rosario ; V. Girijavallabhan ; L. James ; Y.H. Liu ; P. Kirschmeier ; A. Tsarbopoulos ; D. Cesarz

MS based methodology employing electrospray ionization (ESI) is described for the detection of ternary complexes in which SCH 54292 or SCH 54341 and GDP are noncovalently bound to oncogenic ras protein. The observed molecular weights of 19,816 and 19,570 Da confirmed the presence of noncovalent complexes of ras-GDP-SCH 54292 and ras-GDP-SCH 54341, respectively. We have also performed selective chemical modification of lysine residues of the ras protein complex followed by enzymatic digestion and on-line LC-ESI MS peptide mapping to determine protein-drug binding topography. There was a good correlation between nucleotide exchange inhibition as determined by the enzyme assay and evidence of complex formation as determined by MS.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Agouron Pharmaceuticals LLC	-
Neoplasms	Preclinical	US	Schering-Plough Corp.	-

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