Kinases tertiary structure

The second mode of toxicity is postulated to involve the direct interaction of the epidithiodiketopiperazine motif with target proteins, forming mixed disulfides with cysteine residues in various proteins. Gliotoxin, for example, has been demonstrated to form a 1 1 covalent complex with alcohol dehydrogenase [13b, 17]. Epidithiodi-ketopiperazines can also catalyze the formation of disulfide bonds between proxi-mally located cysteine residues in proteins such as in creatine kinase [18]. Recently, epidithiodiketopiperazines have also been implicated in a zinc ejection mechanism, whereby the epidisulfide can shuffle disulfide bonds in the CHI domain of proteins, coordinate to the zinc atoms that are essential to the tertiary structure of that domain, and remove the metal cation [12d, 19],... 

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-... 

On the basis of data presently available, one would conclude that phosphorylation of serine in proteins probably occurs when the serine residues are adjacent to or in close proximity (sequence-wise) to basic or acidic amino acid residues. In the tertiary structure it would be expected that these residues would be near the surface of the protein. Recently, it has been shown for a wide variety of O-phosphoryl proteins that protein substrates of intracellular protein kinases all have a common feature when the caseins are excluded in general, all phosphorylated sites are separated from either lysine or arginine (in two cases, histidine) by no more than two amino acid residues (103a). 

Figure 8.1 Tertiary structure. P-pleated sheets and a-helices fold themselves to form two different creatine kinase (CK) monomers (CK-M and CK-B).

Many opium-derived and other IQs are psychoactive, the best known being the analgesic, addictive, narcotic, opium-derived morphinan alkaloids codeine and morphine (heroin being the semi-synthetic diacetate of morphine). The tertiary or quaternary amine structural component is important for the activity of some Erytkrina alkaloids and bisbenzyliso-quinolines (notably the major curare component (+)-tubocurarine) as antagonists of the nACh-R involved in neuronal excitation of skeletal muscle. The planar disposition of some polycyclic benzophenanthridines enables intercalation (parallel interleaving) between the base pairs of DNA. A variety of naturally occurring and synthetic IQ compounds are protein kinase inhibitors. 

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