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The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to(More)
Chronic myeloid leukemia (CML) is caused by the kinase activity of the BCR-Abl fusion protein. The Abl inhibitors imatinib, nilotinib and dasatinib are currently used to treat CML, but resistance to these inhibitors is a significant clinical problem. The kinase inhibitor bosutinib has shown efficacy in clinical trials for imatinib-resistant CML, but its(More)
Hydrogen bonds are ubiquitous in chemistry and biology. The physical forces that govern hydrogen-bonding interactions have been heavily debated, with much of the discussion focused on the relative contributions of electrostatic vs quantum mechanical effects. In principle, the vibrational Stark effect, the response of a vibrational mode to electric field,(More)
The catalytic activity of the Src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the C terminus (Tyr 527 in c-Src), which is catalyzed by C-terminal Src Kinase (Csk). Given the promiscuity of most tyrosine kinases, it is remarkable that the C-terminal tails of the Src family kinases are the only known targets(More)
The Src family kinases possess two sites of tyrosine phosphorylation that are critical to the regulation of kinase activity. Autophosphorylation on an activation loop tyrosine residue (Tyr 416 in commonly used chicken c-Src numbering) increases catalytic activity, while phosphorylation of a C-terminal tyrosine (Tyr 527 in c-Src) inhibits activity. The(More)
Kinase inhibitors are important cancer drugs, but they tend to display limited target specificity, and their target profiles are often challenging to rationalize in terms of molecular mechanism. Here we report that the clinical kinase inhibitor bosutinib recognizes its kinase targets by engaging a pair of conserved structured water molecules in the active(More)
The physical properties of solvents strongly affect the spectra of dissolved solutes, and this phenomenon can be exploited to gain insight into the solvent-solute interaction. The large solvatochromic shifts observed for many dye molecules in polar solvents are due to variations in the solvent reaction field, and these shifts are widely used to estimate the(More)
The role of electric fields in important biological processes such as binding and catalysis has been studied almost exclusively by computational methods. Experimental measurements of the local electric field in macromolecules are possible using suitably calibrated vibrational probes. Here we demonstrate that the vibrational transitions of phosphate groups(More)
b S Supporting Information ' INTRODUCTION Hydrogen bonding is of fundamental importance for structure, function, and dynamics in a vast number of chemical and biological systems. 1À6 In conventional hydrogen bonds, XÀH 3 3 3 A, a hydrogen atom bridges the proton donor X and proton acceptor A. The donor is usually very electronegative, for example, O or N,(More)
Kinases play a critical role in cellular signaling pathways. Human kinase dysregulation has been linked to a number of diseases, such as cancer, diabetes, and inflammation, and as a result, much of the eeort in developing treatments (and perhaps % of all current drug development eeort) has focused on shutting down aberrant kinases with targeted inhibitors.(More)