Dynamics of human protein kinases linked to drug selectivity [preprint]

Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinases Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Aurora A. Using a combination of biophysical techniques, we propose a universal drug-binding mechanism, that rationalizes selectivity, affinity and long on-target residence time for kinase inhibitors. These new concepts, where protein dynamics in the drug-bound state plays the crucial role, can be applied to inhibitor design of targets outside the kinome

Technical Aspects of the Translation of Genesis of Martin Buber amd Franz Rosenzweig

Thesis (Ph.D.)--Brandeis University, 1975.School code: 0021

The Making of a Reform Rabbi

Thesis (Ph.D.)--Brandeis University, 1971.School code: 0021

From the margins to the mainstream: Labor Zionism and American Jews, 1919-1945

This dissertation stakes a claim for the importance of Labor Zionism in the American Jewish context between 1919 and 1945. It argues that Labor Zionism, with its base in Palestine and satellite organization in the United States, had a profound impact on American Zionism and American Jews.The disjunction between Labor Zionism's relatively small size and disproportionate influence in the United States raises the question why, if the movement was so ideologically important, was it so institutionally and numerically weak? Its core groups were never more than half the size of other Zionist groups. Yet beginning in the middle 1930s, Labor Zionism played an increasingly important role in the development of American Zionism. This was due, in large measure, to Labor's ascendance in the Yishuv and the movement's concomitant rise to hegemony in the World Zionist Organization and Jewish Agency. As a result, the Labor Zionist movement in the United States profited considerably.During the interwar years American Labor Zionism became a hub of social, cultural and political activity. By the early 1940s it effectively defined American Jewry's emergent post-war agenda. This phenomenon derived from a lengthy process of discussion and debate in the American Zionist arena and the wider American Jewish community. It was influenced by developments in Palestine as well as the tragic situation of European Jewry. Zionists, non-Zionists and sympathetic Jews in the United States all gravitated to the Labor Zionist program of building the Jewish National Home. The Labor movement in Palestine commanded a vast socioeconomic infrastructure that made the establishment of the Jewish state possible. Finally, in 1943 organized American Jewry adopted a public policy that called for the creation of an independent Jewish commonwealth in Palestine.Thesis (Ph.D.)--Brandeis University, 1996.School code: 0021