Mutant kinases, binding sites

Cheetham SC, Crompton MR, Katona CL, Horton RW (1990) Brain 5-HTl binding sites in depressed suicides. Psychopharmacology (Berl) 102 544-548 Chen C, Rainnie DC, Greene RW, Tonegawa S (1994) Abnormal fear response and aggressive behavior in mutant mice deficient for alpha-calcium-calmodulin kinase II. Science 266 291-294... 

Black, M. E., and Loeb, L. A. (1993). Identification of important residues within the putative nucleoside binding site of HSV-1 thymidine kinase by random sequence selection analysis of selected mutants in vitro. Biochemistry, 32, 11618—11626. 

Metabolic Effects of Mutant Enzymes Predict and explain the effect on glycogen metabolism of each of the following defects caused by mutation (a) loss of the cAMP-binding site on the regulatory subunit of protein kinase A (PKA) (b) loss of the protein phosphatase inhibitor (inhibitor 1 in Fig. 15-40) (c) overexpression of phosphorylase b kinase in liver (d) defective glucagon receptors in liver. 

Figure 3.6 Replacing a bulky amino acid with glycine in the ATP-binding site of a kinase enlarges the site. ATP binding and catalytic activity are unaffected. The nonselective kinase inhibitor can now be modified to create a molecule that selectively blocks the mutant enzyme.

The bcr-abl fusion gene produces a mutant tyrosine kinase that is involved in both the increased proliferation of the CML clone, and in the reduction in FAS-mediated apoptosis. The characterization of the adenosine triphosphate (ATP) binding site on the tyrosine kinase has led to a new class of inhibitors. The first of these inhibitors, imatinib mesylate (Gleevec), was approved in 2001 for patients in chronic phase who had failed interferon alfa (IFN-a), and in accelerated phase or blast crisis. It obtained additional FDA approval in 2002 for first-line treatment in newly diagnosed CML. The clinical results associated with imatinib have changed the way CML is treated, and will be discussed in more detail under the treatment section of this chapter. "... 

Hagemann, H. Marcillat, O. Buchet, R. Vial, C., Magnesium-adenosine diphosphate binding sites in wild-type creatine kinase and in mutants Role of aromatic residues probed by Raman and infrared spectroscopies. Biochemistry 2000, 39(31), 9251-6. 

---