Protein kinase family

We have previously calculated conformational free energy differences for a well-suited model system, the catalytic subunit of cAMP-dependent protein kinase (cAPK), which is the best characterized member of the protein kinase family. It has been crystallized in three different conformations and our main focus was on how ligand binding shifts the equilibrium among these ([Helms and McCammon 1997]). As an example using state-of-the-art computational techniques, we summarize the main conclusions of this study and discuss a variety of methods that may be used to extend this study into the dynamic regime of protein domain motion. 

The abundance of structural information has led to a significant increase in the use of structure-based methods both to identify and to optimise inhibitors of protein kinases. The focus to date has centred upon small molecule ATP-competitive inhibitors and there are numerous examples of protein-ligand complexes available to guide design strategies. ATP binds in the cleft formed between the N- and C-terminal lobes of the protein kinase, forming several key interactions conserved across the protein kinase family. The adenine moiety lies in a hydrophobic region between the jS-sheet structure of subdomains I and II and residues from subdomains V and VIb. A... 

Hanks, S. K., Quinn, A. M., and Hunter, T. (1988). The protein kinase family conserved features and deduced phylogeny of the catalytic domains. Science 241 42-52. 

Poteet-Smith, C. E., Smith, J. A., Lannigan, D. A., Freed, T. A., and Sturgill, T. W. (1999). Generation of constitutively active p90 ribosomal S6 kinase in vivo. Implications for the mitogen-activated protein kinase-activated protein kinase family. J. Biol. Chem. 274, 22135-22138. 

Figure 3.5. Aminoglycoside kinases are members of the protein kinase family. Comparison of c-AMP-dependent protein kinase (cAPK) to APH(3 )-IIa and APH(3 )-IIIa. (A) cAPK (catalytic domain) from Mus musculus (pdb ID 2CPK). (B) APH(3 )-IIa from Klebsiella pneumoniae (pdb ID 1ND4). (C) APH(3 )-IIIa from Enterococcus faecalis (pdb ID 1L8T).

Like most of the Ser/Thr-specific protein kinase family, the protein kinase C family also shows significant heterogeneity. At the present time, at least 12 different subtypes of protein kinase C have been discovered in mammals, based on different criteria such... 

Kostich, M., English, J., Madison, V., et al. (2002) Human members of the eukaryotic protein kinase family. Genome Biol 3(9), 0043.1-0043.12. 

The protein kinase family encompasses more than three hundred members of critically important enzymes, each one with a specific role or function within the cell. These enzymes, ATP-phosphotransferases, recognize target proteins and through the phosphorylation of specific sites either activate or deactivate a particular pathway of signal transduction. Many of these signaling pathways are associated with cell surface receptors, which are located in the membranes that surround cells. The difference between the families of protein kinases is that they have different targets and generally fall into two major classes ... 

In the past several years there has been an explosion of structural studies within the protein kinase family [1-8]. These studies, initiated by the crystal structure of Protein Kinase A [9-12] (CAPK) have shown that all members of the protein kinase family fold into a uniform three-dimensional catalytic core. Yet this uniform three-dimensional fold exhibits both different surface charges and at least two major conformations. 

In this chapter, we describe a simple and robust approach for representing and analyzing three-dimensional protein-ligand complexes called SIFt (Structural Interaction Fingerprint) [6, 7]. We will show how this method can be applied to organizing and analyzing the structural information within the protein kinase family and also how this can be applied to virtual screening for inhibitors. 

Schneider AG, Mercereau-Puijalon O (2005) A new Apicomplexa-specific protein kinase family multiple members in Plasmodium falciparum, all with an export signature. BMC Genomics 6 30... 

Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Stanton VP, Thirion JP, Hudson T, et al (1992) Molecular basis of myotonic dystrophy expansion of a trinucleotide (CTG) repeat at the 3 end of a transcript encoding a protein kinase family member. Cell... 

The reader may want to look up the, Protein Kinase Resource (PKR). This is a web-accessible compendium of information on the protein kinase family of enzymes. 

Protein kinase family Rat protein kinase C-a ITBN Cysp 2 CysL 21 HiSa/i 2 CySba... 

Phosphorylation is a common mechanism resulting in resistance to the aminoglycoside antibiotics. This chemical strategy also has been associated with resistance to the macrolides such as erythromycin, the tuberactinomycins such as viomycin, and chloramphenicol. The aminoglycoside kinases share 3D structural similarity with the Ser/Thr/Tyr protein kinase family (36), and the conservation of kinase signature sequences in macrolide... 

Chloramphenicol phosphotransferase from the producing bacterium Streptomyces venezuelae (47) is unrelated to the protein kinase family but rather shows more similarity to small-molecule kinases such as shikimate kinase (48). Analogous to the CAT strategy, phosphorylation occurs at the hydroxyl position 3, blocking this essential group from interacting with the ribosome (Fig. 10). 

Cyclic nucleotide regulated protein kinase family = Adenylyl cyclases = A-kinase anchor proteins = Atypical PKCs = Atrial natriuretic peptide = Adenosine 5 -triphosphate = Brain natriuretic peptide = Ca Vcalmodulin-dependent kinases = Cyclin-dependent kinases = Ca -dependent protein kinase = Casein kinase I = Casein kinase II = Dcd-like kinase... 

In contrast to this polyspecific ABPP probe suitable for profiling a large fraction of the protein kinase family, several other approaches have been introduced, which focus on specific subfamilies. Wortmannin, for example, is a potent natural product specific for the inhibition of phosphoinositide 3- and polo-like kinases in vitro and in vivo. Its role in ABPP probe design will be discussed in the natural product-derived probe section (Section 9.17.3.3)97 98... 

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