Catalytic domain binding pocket

The class III deacetylases, named sirtuins, are structurally and functionally different from other HDACs. In contrast to the zinc-dependent deacetylation of classic HDACs, sirtuins depend on NAD" to carry out catalytic reactions. A variety of sirtuin crystal structures have been published over the past few years. The structures of human Sirt2 and SirtS as well as several bacterial Sir2 proteins could be derived, whereas no 3D structure is available for Sirtl and the other subtypes [69]. All solved sirtuin structures contain a conserved 270-amino-acid catalytic domain with variable N- and C-termini. The structure of the catalytic domain consists of a large classic Rossmann fold and a small zinc binding domain. The interface between the large and the small subdomain is commonly subdivided into A, B and C pockets. This division is based on the interaction of adenine (A), ribose (B) and nicotinamide (C) which are parts of the NAD" cofactor. (Figure 3.5) Whereas the interaction of adenine and... 

Mithramydn A binds to GC-rich or CG-rich DNA sequences and blocks DNMT methylation activity. Docking of mithramycin A into the DNMTl catalytic domain indicates that the trisaccharide of the inhibitor can fit into the putative cytosine pocket and the aglycon core is bound betv een the two arms that fasten the hemimethylated DNA. 

While no MEK apo structures have been published, comparisons to the catalytic domains of similar kinases reveal a number of differences versus the tertiary structure of MEKl. Relative to a crystal structure of PKA, there is an outward rotation of the N-terminal portion of hehx C by approximately 10 A and the formation of a short, two-turn a-hehcal segment of the activation loop. Both of these changes give rise to the allosteric binding pocket which enables the unique binding mode. Inhibitors such as PD318088 stabi-... 

Figure 6 Mechanisms of translesion synthesis, (a) Activation mechanism of Pol V during translesion synthesis. Pol V is a heterotrimer composed of subunits UmuC, D 2 UmuC is the catalytic domain, and UmuD is the product of RecA mediated proteolysis. Translesion synthesis by Pol V is activated by the presence of a RecA filament in trans. (b) Model of DNA polymerase switching during translesion synthesis. Pol III and Pol IV each bind to a p protomer at a conserved hydrophobic protein binding pocket (QL[S/D]LF). 1. Pol III is arrested at the site of DNA damage, whereas Pol IV is held in an inactive state away from the DNA. 2. Pol IV gains hold of the primer terminus from Pol III at the stall site Pol III is now held away from the DNA. 3. Pol IV extends the DNA past the lesion. 4. Pol III regains hold of the primer terminus from Pol IV.

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