Antiproliferative activity and apoptosis induction,of organo-antimony(III)–copper(I) conjugates,against human breast cancer cells

Molecular Diversity - Three known organo-antimony(III)–copper(I), mixed-metal small bioactive molecules (SBAMs) of formula [Cu(tpSb)3Cl] (1), [Cu2(tpSb)4Br2] (2) and [Cu2(tpSb)4I2] (3)...     

A phosphoarginine containing peptide as an artificial SH2 ligand

We have developed a synthesis of phosphoarginine containing peptides using a bis(2,2,2-trichloroethyl) protected phosphoarginine derivative as building block. Binding studies and computer modelling demonstrate the ability of the SH2 domain from Src kinase to recognize a phosphoarginine-containing peptide in a phosphoryl group-dependent manner.     

Designing allosteric control into enzymes by chemical rescue of structure

Ligand-dependent activity has been engineered into enzymes for purposes ranging from controlling cell morphology to reprogramming cellular signaling pathways. Where these successes have typically fused a naturally allosteric domain to the enzyme of interest, here we instead demonstrate an approach for designing a de novo allosteric effector site directly into the catalytic domain of an enzyme. This approach is distinct from traditional chemical rescue of enzymes in that it relies on disruption and restoration of structure, rather than active site chemistry, as a means to achieve modulate function. We present two examples, W33G in a β-glycosidase enzyme (β-gly) and W492G in a β-glucuronidase enzyme (β-gluc), in which we engineer indole-dependent activity into enzymes by removing a buried tryptophan side chain that serves as a buttress for the active site architecture. In both cases, we observe a loss of function, and in both cases we find that the subsequent addition of indole can be used to restore activity. Through a detailed analysis of β-gly W33G kinetics, we demonstrate that this rescued enzyme is fully functionally equivalent to the corresponding wild-type enzyme. We then present the apo and indole-bound crystal structures of β-gly W33G, which together establish the structural basis for enzyme inactivation and rescue. Finally, we use this designed switch to modulate β-glycosidase activity in living cells using indole. Disruption and recovery of protein structure may represent a general technique for introducing allosteric control into enzymes, and thus may serve as a starting point for building a variety of bioswitches and sensors.     

Depth profiling the thermal reflection coefficient of an opaque solid via an inverse thermal wave scattering theory based on the Method of Images

A new formulation of the inverse problem of depth profiling the thermal properties of an opaque solid based on one-dimensional photo-generated thermal waves is presented. The inverse problem as posed is linear in a set of lumped thermal reflection coefficients which account for the return of energy to the surface by all significant heat conduction channels. An analysis based on the Method of Images relates these coefficients to individual values of the interface thermal reflection coefficients in the material. No weak backscattering assumption is invoked to linearize the problem. The method yields a unique solution subject to a given condition of regularization. Solutions recovered by the method are stable at experimentally feasible error levels. Received: 27 September 1999 / Published online: 16 June 2000     

Method of Images direct mapping of one-dimensional heat flow patterns in an arbitrarily layered solid

A new method for direct analysis and visualization of one-dimensional heat flow patterns in an arbitrarily layered impulse-heated solid is presented. This analysis is based on the Method of Images in which the surface temperature/time response is described as the superposition of a free medium temperature field and additional image field contributions which account for the effects of thermal reflection and damping at subsurface interfaces. Through the introduction of a simple set of constraint rules, all sequences of thermal reflection and transmission at sample interfaces which return significant energy to the material surface in a given observation time may be systematically mapped and directly visualized.