Adenine pocket

The lipophilic environment created by residues that form the adenine-binding pocket extends sufficiently beyond the opening of the pocket to create an additional lipophilic binding area in front of the adenine. This pocket may not be accessible to inhibitors that bind into tightly closed adenine pockets. Inhibitor accessibility to this pocket may also be restricted for some kinase families. For example, the AGC family kinases (PKA, PKC, AKT) have a C-terminal tail that extends back into N-terminal domain and caps the adenine site with a phenylalanine (see Section 2.2.3.3). Inhibitor-kinase structures that bind an aryl ring in this site include 10 in CDK2 (Fig. 2.5 B) [67], 9 in CDK2 [66], and 17 (Scheme 2.4) in p38... 

Overlaying the structures of the adenine-pocket binding fragments with the substrate-pocket binding fragments revealed that they were separated by about... 

Pro26 (Serl8), Tyr27 (19), Phe28 (20), and Prol53 (144), residues contributing to the hydrophobic pocket for the adenine ring of SAM ... 

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... 

Fig. 7. DOCK site point breakdown for the kinase receptor study. Three primary critical regions were defined (1) adenine acceptor zone, (2) adenine donor zone, (3) kinase ATP inhibitor rear hydrophobic pocket binding region. Adapted from ref. 70.

The adenine ring of the coenzyme is bound in a hydrophobic pocket with its amino group pointed out into the solvent. A second structural domain holds additional catalytic groups needed to form the active site. 

The modes of action of different alkaloids are diverse. For example, nicotine binds to and affects nicotinic acetylcholine receptors and shows toxicity. A recent molecular 3D model suggests that both acetylcholine and nicotine bind to the same pocket formed in a nicotinic acetylcholine receptor.15 Morphine binds to and activates opioid receptors, transmembrane-spanning G protein-coupled receptors, in the central nervous system of humans.16 Caffeine, which is structurally similar to adenine, inhibits cyclic AMP phosphodiesterase activity and inhibits the degradation of cAMP, thus exerting a toxic effect on insects 17 in human beings, binding of caffeine to the adenosine A2A receptor induces wakefulness.18 Atropine binds to muscarinic acetylcholine receptors, competing with acetylcholine, and blocks neurotransmission.1... 

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