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Document Figure 2 The diagrams of the Cα trace of the five kinases, cAPK, CDK2, CDK2-CYCLIN, IR, MAP. The thin line represents crystallographically determined homologous regions of the five kinases (R. Karlsson and J.M. Sowadski, personal communication). Page 217 crystals of bovine heart mammalian cAPK [15,16]. A comparison between the two structures has shown that there is rotation of the upper lobe by 15 degrees and a translation of 1.9 Å in the mammalian structure, which results in the opening of the nucleotide binding cleft. The motion of this lobe, which includes His87, one of the ligands to Thr197 [15], indicates that the phosphorylation of this site will be important for conformational diversity of the upper lobe. This is confirmed by the varying degrees of displacement of the upper lobe of all structures of the inactive unphosphorylated protein kinases (see review [17]). The lower lobe of the enzyme starts with helix D, which is followed by helix E and β-strands 6 and 7. The catalytic loop connecting both strands consists of a critical set of residues with Tyr164 and Arg165 at the beginning of the loop. The Tyr164 residue forms a hydrogen bond with invariant Asp220. The Arg165 residue, which is present in a great majority of protein kinases, provides two hydrogen bonds to the oxygens of the phosphate of Thr197. Invariant Asp166 (the catalytic base) and Asn171 (the ligand to one of the metal sites) are also located within this loop. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_217.html (1 of 2) [4/5/2004 5:07:00 PM]
Document Page 218 The catalytic loop is the region of divergence between Ser/Thr and Tyr kinases. In cAPK and all Ser/Thr Kinases, Lys168 interacts with the γ phosphate of ATP during catalysis [12]. The role of Lys is replaced by Arg [9] and the insulin receptor tyrosine kinase structure [3] shows Arg1136 in a similar position as Lys168 in the active site of cAPK. The catalytic loop and β-strand 7 are followed by β-strand 8 and a short DFG conserved motif. This conserved motif consists of invariant Asp184, a ligand to the metal site, and invariant Phe185. The DFG motif is followed by β-strand 9, an activation loop that includes Thr197. The activation loop differs considerably among unphosphorylated kinases, CDK-2, ERK-2, and insulin receptor kinase. Furthermore, two crystal structures, twitchin protein kinase [2] and phosphorylase kinase [5], both lack a phosphorylation site in this region. In the first structure, twitchin protein kinase, Thr197 and Arg165, are replaced by hydrophobic residues, Val6098 and Leu6062 respectively [2]. This was predicted using modeling [18] and subsequently confirmed by the three-dimensional structure. In the second structure, phosphorylase kinase, the Thr197 is replaced by Glu182, which interacts with Arg148 [5]. Hence, in both structures the regulatory function of the phosphorylation site is replaced by a stable scaffold secured by either hydrophobic or electrostatic interactions. Since it has been shown that this loop provides a stable template for PKI(5–24) binding in cAPK, the status of phosphorylation of the activation loop critically affects the substrate binding. This is demonstrated in c-Src, a homolog of the Rous Sarcoma virus oncogene by mutation of Arg385, which is predicted to interact with the phosphate of Tyr416, and results in loss of activity toward the exogenous substrate [19]. The activation loop is followed by a P+1 loop which accommodates the P+1 site of the substrate. The P+1 loop is followed by invariant Glu208, which forms a salt bridge with invariant Arg280. This conserved pair plays a structural role and as the structure of CK-1 [16] shows, it can be replaced by other charged residues that maintain the same fold of the lower lobe. The P+1 loop and Glu 208 are followed by helix F consisting of invariant Asp220, followed by helices G, H, and I. The helix J and the C-terminal tail of cAPK, which are absent in other protein kinases, undergo a large motion during the cleft opening. The opening of the cleft results in loss of hydrogen bonds provided by the γ phosphate of ATP and the peptide that would bridge the lower and upper lobe of the enzyme. The motion of the upper domain increases the accessibility of the ATP binding site and one can envision that in the “open” conformation ATP binds. Yet, in the “closed” conformation ATP and its γ phosphate are positioned for a nucleophilic attack on the substrate. The motion of this lobe—which includes His87, one of the ligands to Thr197 [15]—indicates that the phosphorylation of this site will be important for conformational diversity of the upper lobe. This is confirmed by the varying degrees of displacement of the upper lobe http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_218.html [4/5/2004 5:07:03 PM]
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