Kinase structures

Vonrhein et al. 1995] Vonrhein, C., Schlauderer, G.J., Schulz, G.E. Movie of the structural changes during a catalytic cycle of nucleoside monophosphate kinases. Structure 3 (1995) 483-490. 

A number of kinase structures have been determined in various catalytic states. For example, structures of the cyclin-dependent kinase, CDK2, in its inactive state and in a partially active state after cyclin binding have been discussed in Chapter 6. The most thoroughly studied kinase is the cyclic AMP-dependent protein kinase the structure of both the inactive and the active... 

Johnson, L.N., Noble, M.E.M., Owen, D.J. Active and inactive protein kinases structural basis for regulation. 

Hubbard SR, Till JH (2000) Protein tyrosine kinase structure and function. Annu Rev Biochem 69 373-398... 

Each of the pharmacophore queries consisted of one donor, one acceptor and one of the two hydrophobic points indicated in Figure 1.16. The directionality of hydrogen bonds was inferred from the X-ray structure and reasonably loose tolerances of 1.5 A were used for donor-acceptor distances and 2-2.5 A to the hydrophobe were chosen to allow for the flexibility seen across kinase structures and to maximise the diversity amongst the identified fragments. Four pharmacophore queries were completed and the results were combined. The chosen fragments were further filtered by molecular weight (between 150 and 250), 51og P (between 2.5 and —2.5) and the presence of... 

ErbB (or HER in the human). There are four ErbB receptors that form homo- or heterodimers in various combinations upon ligand binding. Specific NRG isoforms preferentially interact with different ErbB dimers. The ErbB receptors are ligand-activated tyrosine kinases structurally similar to the EGF receptor. 

Wang Z., Canagarajah B.J., Boehm J.C., Kassisa S., Cobb M.H., Young P.R., Abdel-Meguid S., Adams J.L., Goldsmith E.J. Structural basis of inhibitor selectivity in MAP kinases. Structure 1998, 6, 1117-1128. 

Kinase domain Regulated by kinase function Regulated by kinase structure... 

Also related to Src kinase structural biology have been studies on two SFKs, namely Lck and Fyn. Importantly, the X-ray structure of Lck kinase was the first SFK determined [64] as complexes with AMP-PNP, staurosporine and PP2. Furthermore, a Fyn kinase-staurosporine complex has been recently described [65]. Extrapolating from the above Src kinase inhibitor crystal structures with respect to the hydrophobic specificity pocket and the active conformation of the protein to bind ATP-competitive inhibitors of varying templates and functional group elaboration, a working hypothesis of known Src kinase inhibitors (vide infra) can be suggested (Fig. 4). 

Fig. 5. Superposition of 26 kinase structures via their conserved structural elements, with ATP binding site highlighted. Adapted from ref. 61.

The catalytic domain of protein kinase A has a two lobe structure, composed of a smaller lobe with a large portion of P-sheet structures and a larger lobe that is mostly a-helical. All Ser/Thr- and Tyr-specific protein kinases structurally characterized to date show a similar domain structure. 

Fig. 8.7. Structure of the catalytic domain of the insulin receptor. The crystal structure of the tyrosine kinase domain of the insulin receptor (Hubbard et al., 1994) has a two-lobe structure that is very similar to the structure of the Ser/Thr-specific protein kinases. Structural elements of catalytic and regulatory importance are shown. The P loop mediates binding of the phosphate residue of ATP the catalytic loop contains a catalytically essential Asp and Asn residue, found in equivalent positions as conserved residues in many Ser/Thr-specific and Tyr-specific protein kinases. Access to the active center is blocked by a regulatory loop containing three Tyr residues (Tyrll58, Tyrll62 and Tyrll63). Tyrll62 undergoes autophosphorylation in the course of activation of the insulin receptor. MOLSKRIPT representation according to Kraulis, (1991).

The catalytic loop is the region of divergence between Ser/Thr and Tyr kinases. In cAPK and all Ser/Thr Kinases, Lysl68 interacts with the phosphate of ATP during catalysis [12]. The role of Lys is replaced by Arg [9] and the insulin receptor tyrosine kinase structure [3] shows Argl 136 in a similar position as Lys 168 in the active site of cAPK. 

In the analysis of the structural data of other protein kinases, it is noted that only cAPK has been crystallized with its specific peptide inhibitor. Nevertheless, three other structures of protein kinases compared with the structure of the cAPK-PKI complex provide substantial evidence for the conservation of the substrate binding cleft. The substrate binding cleft of the phosphorylase kinase structure has been analyzed in detail and it is clear that all amino acids of the known specific substrate can be built into the PKI model and all required corresponding charges can be found in the cleft of the phosphorylase kinase structure. In the CK-1 structure determined without a peptide, the requirement of the peptide specificity resides on the P-3 site, which has to be phosphorylated. An analysis of the surface charges of the cleft of the CK-1 structure reveals the exact correspondence of the residues required to interact with a phosphorylated substrate at this site. 

Rubio, V. Cervera, J. The carbamoyl-phosphate synthase family and carbamate kinase structure-function studies. Biochem. Soc. Trans., 23, 879-883 (1995)... 

Kenyon, G.L. Reed, G.H. Creatine kinase structure-activity relationships. Adv. Enzymol. Relat. Areas Mol. Biol., 54, 367-426 (1983)... 

Yan, H. Tsai, M.-D. Nucleoside monophosphate kinases structure, mechanism, and substrate specificity. Adv. EnzymoL Relat. Areas Mol. Biol., 73, 103-134 (1999)... 

Janin, J. Deville-Bonne, D. Nucleoside-diphosphate kinase structural and kinetic analysis of reaction pathway and phosphohistidine intermediate. Methods EnzymoL, 354, 118-134 (2002)... 

Fioravanti, E. Haouz, A. Ursby, T. Munier-Lehmann, H. Delarue, M. Bourgeois, D. Mycobacterium tuberculosis thymidylate kinase structural studies of intermediates along the reaction pathway. J. Mol. Biol., 327, 1077-1092 (2003)... 

Fig. 10.2 The procedure used to generate a p-SIFt from a set of SIFts is illustrated in (a). The profile shown corresponds to the p-SI Ft generated from the 93 kinase structures using all seven bits to compute the SIFts shown in (b). The p-SIFt is annotated with a topmost bar delineating the general kinase structural features for that portion of the...

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