Three-dimensional kinases

A worldwide repository for the processing and distribution of three-dimensional biologic macromolecular structure data.) The Protein Kinase Resource http //pkr.sdsc.edu/html/index. shtml... 

Fig. 3. Three-dimensional model of human phosphoglycerate kinase based on the structure of horse enzyme. Positions of the molecular abnormalities of variant enzymes are also shown.

A3. Allen, S., and Muirhead, H Refined three-dimensional structure of cat-muscle (Ml) pyruvate kinase at a resolution of 2.6 A. Acta Crystallogr., Sect. D Biol. Crystallogr. D52, 499-504 (1996). 

With the advance of X-ray crystalography and the ability to determine the three dimensional structure of the kinase with the bound inhibitor, drug design has become more precise and rational. The three dimensional structures of a two tyrosine kinases complexed with a kinase inhibitor have already been solved ... 

A metal-nucleotide complex that exhibits low rates of ligand exchange as a result of substituting higher oxidation state metal ions with ionic radii nearly equal to the naturally bound metal ion. Such compounds can be prepared with chromium(III), cobalt(III), and rhodi-um(III) in place of magnesium or calcium ion. Because these exchange-inert complexes can be resolved into their various optically active isomers, they have proven to be powerful mechanistic probes, particularly for kinases, NTPases, and nucleotidyl transferases. In the case of Cr(III) coordination complexes with the two phosphates of ATP or ADP, the second phosphate becomes chiral, and the screw sense must be specified to describe the three-dimensional configuration of atoms. 

Howes AL, Chiang GG, Lang ES et al (2007) The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther 6 2505-2514... 

Designing specific enzyme inhibitors on a rational basis when one does not have a detailed three-dimensional crystal structure to which to relate is a rather sophisticated challenge. Some viable approaches to such a challenge are discussed in a review chapter by Santi and Kenyon (91) This discussion will focus on our rationale for the design of an affinity label for creatine kinase, namely N-(2,3-epoxypropyl)-N-amidinoglycine (epoxycreatine ) ... 

N-Myristoylation is achieved by the covalent attachment of the 14-carbon saturated myristic acid (C14 0) to the N-terminal glycine residue of various proteins with formation of an irreversible amide bond (Table l). 10 This process is cotranslational and is catalyzed by a monomeric enzyme called jV-myri s toy 11ransferase. 24 Several proteins of diverse families, including tyrosine kinases of the Src family, the alanine-rich C kinase substrate (MARKS), the HIV Nef phosphoprotein, and the a-subunit of heterotrimeric G protein, carry a myr-istoylated N-terminal glycine residue which in some cases is in close proximity to a site that can be S-acylated with a fatty acid. Functional studies of these proteins have shown an important structural role for the myristoyl chain not only in terms of enhanced membrane affinity of the proteins, but also of stabilization of their three-dimensional structure in the cytosolic form. Once exposed, the myristoyl chain promotes membrane association of the protein. 5 The myristoyl moiety however, is not sufficiently hydrophobic to anchor the protein to the membrane permanently, 25,26 and in vivo this interaction is further modulated by a variety of switches that operate through covalent or noncovalent modifications of the protein. 4,5,27 In MARKS, for example, multiple phosphorylation of a positively charged domain moves the protein back to the cytosolic compartment due to the mutated electrostatic properties of the protein, a so-called myristoyl-electrostatic switch. 28 ... 

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. 

Thompson, T.B. Thomas, M.G. Escalante-Semerena, J.C. Rayment, L Three-dimensional structure of adenosylcobinamide kinase/adenosylcobina-mide phosphate guanylyltransferase from Salmonella typhimurium determined to 2.3 A resolution. Biochemistry, 37, 7686-7695 (1998)... 

Stehle, T. Schultz, G.E. Three-dimensional structure of the complex of guanylate kinase from yeast with its substrate GMP. J. Mol. Biol., 211, 249-254 (1990)... 

There are two prominent types of mammalian cAMP-dependent protein kinases.51 61 The catalytic subunit is identical for both the 41-kDa peptide as isolated from beef heart has 350 residues and an N terminus blocked by a myristoyl (tetradecanoyl) group.62 One phosphoserine and one phosphothreonine are also present.51 The 50-kDa regulatory subunits vary in size and may also be subject to additional regulation by phosphorylation.63 Three-dimensional structures are known for both the catalytic62 64 65 and the regulatory66 subunits. A cyclic GMP (cGMP)-activated protein... 

The powerful cancer suppressor, p53, which is also described in Box 11-D, in some way senses DNA damage. It prevents passage through the G checkpoint and also through the G2 checkpoint if the DNA has not been adequately repaired.496 497 Protein p53, whose three-dimensional structure is known,500 501 binds to DNA and also induces transcription of genes that cause arrest of the cell cycle. It may also induce cell death (apoptosis), a process that may also require the protein product of protooncogene c-mi/c.502 505 A variety of protein kinases and phosphatases act on p53 and influence its activity.506... 

In fact, kinetic studies of the GTP-dependent avian mitochondrial enzyme indicate two metal-binding sites, one on the polyphosphate group of the bound GTP and one on carboxylate side chains of the protein.252 255 The three-dimensional structure of the ATP-dependent E. coli enzyme reveals a nucleotide binding site similar to the ATP site of adenylate kinase (Fig. 12-30).256 A definite binding site for C02 is also present in the enzyme.257... 

Thiosulfate cyanide sulfurtransferase symmetry in 78 TTiiouridine 234 Three-dimensional structures of aconitase 689 adenylate kinase 655 aldehyde oxido-reductase 891 D-amino acid oxidase 791 a-amylase, pancreatic 607 aspartate aminotransferase 57,135 catalytic intermediates 752 aspartate carbamyltransferase 348 aspartate chemoreceptor 562 bacteriophage P22 66 cadherin 408 calmodulin 317 carbonic acid anhydrase I 679 carboxypeptidase A 64 catalase 853 cholera toxin 333, 546 chymotrypsin 611 citrate synthase 702, 703 cutinase 134 cyclosporin 488 cytochrome c 847 cytochrome c peroxidase 849 dihydrofolate reductase 807 DNA 214, 223,228,229, 241 DNA complex... 

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