Stc Case Study

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1) The Philadelphia chromosome is chromosome 22, which has undergone a reciprocal translocation with chromosome 9, such that the long arm of chromosome 22 has been replaced with the long arm of chromosome 9. This chromosome is relevant to cancer because the long arm of chromosome 9 contains human c-abl oncogene, which becomes fused to the breakpoint cluster region (bcr) in the Philadelphia chromosome, following translocation. Presence of this bcr-abl gene fusion produces a poorly regulated tyrosine kinase, which results in a much higher level of cell proliferation. The action of this tyrosine kinase results in chronic myelogenous leukemia (CML) symptoms, such as overproduction of white blood cells.

2) Opposed to structural data alone, NMR
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This will result in the substrate concentration remaining relatively constant, while only the concentration of the enzyme changes over time. These conditions result in the kinetic order to be the same with respect to enzyme concentration and with time; thus, mimicking first-order kinetics.

3b) A non-linear response is observed here because the binding of enzyme to substrate does not follow simple pseudo-first-order kinetics, but instead there is a two-step process involving rate-limiting changes in protein conformation. These findings support the previously proposed model of substrate binding, in that there is a fast step of enzyme binding to substrate, followed by a slow conformational change in the enzyme once bound to substrate. The plateau in the observed rates indicates the maximal rate at which enzyme can bind to substrate, with Abl binding with a maximal rate of 20 s-1 and Src binding with a maximal rate of 2 s-1.

4) For Abl, the indicated residues are within the C lobe of the enzyme, and are not in direct contact with Gleevec when it is bound. For Src, the indicated residues are within the N lobe of the enzyme, and within the Gleevec binding site, such that they may be making direct contact with Gleevec. Since these residues are within the Gleevec binding region, they demonstrate the complex, two-step, fast and slow exchange that is occurring with Src; whereas, the residues indicated in Abl are not

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