Modulation of protein function

Phosphorylation is the reversible process of introducing a phosphate group onto a protein. Phosphorylation occurs on the hydroxyamino acids serine and threonine or on tyrosine residues targeted by Ser/Thr kinases and tyrosine kinases respectively. Dephosphorylation is catalyzed by phosphatases. Phosphorylation is a key mechanism for rapid posttranslational modulation of protein function. It is widely exploited in cellular processes to control various aspects of cell signaling, cell proliferation, cell differentiation, cell survival, cell metabolism, cell motility, and gene transcription. 

In chemogenomics and drug discovery, the most challenging task is to find small molecule modulators of protein function that specifically modulate the protein function of interest. Combinatorial chemistry has emerged as a powerful tool to address this problem by generation of large compound... 

Compound libraries as sources for small molecule modulators of protein function... 

The ligand binding or catalytic sites are the most relevant parts of a protein domain for the development of small molecules as modulators of protein function. There is evidence that proteins with conserved folds often also have their functional sites on the same topological location. In some cases a remarkable conservatism in functional sites can be observed. This is true for the example described later in this review on similarity of Cdc25A phosphatase, acetylcholinesterase (AChE) and 1 Ifl-hydroxysteroid dehydrogenases (1 l HSD) (Fig. 9). Nevertheless, it should be stressed that the correlation patterns of amino acid sequence, protein fold and protein function remain a matter of debate. Moreover, a vast number of specific functions can be carried out by the limited number of protein domains due to the high amino acid diversity of proteins with similar folds. " ... 

As discussed for N-myristoylation and S-prenylation, even S-acylation of proteins with a fatty acid which in the vast majority of cases is the C16 0 palmitic acid, plays a fundamental role in the cellular signal-transduction process (Table l). 2-5 14 While N-myristoylation and S-prenylation are permanent protein modifications due to the amide- and sulfide-type linkage, the thioester bond between palmitic acid and the peptide chain is rather labile and palmi-toylation is referred to as a dynamic modification. 64 This reversibility plays a crucial role in the modulation of protein functions since the presence or absence of a palmitoyl chain can determine the membrane localization of the protein and can also be used to regulate the interactions of these proteins with other proteins. Furthermore, a unique consensus sequence for protein palmitoylation has not been found, in contrast to the strict consensus sequences required for N-myristoylation and S-prenylation. Palmitoylation can occur at N- or C-terminal parts of the polypeptide chain depending on the protein family and often coexists with other types of lipidation (see Section 6.4.1.4). Given the diversity of protein sequences... 

Phosphorylation on serine, threonine, and tyrosine residues is an extremely important modulator of protein function. Phosphorylation can be analyzed by mass spectrometry with enrichment of compounds of interest using immobilized metal affinity chromatography and chemical tagging techniques, detection of phosphopep-tides using mass mapping and precursor ion scans, localization of phosphorylation sites by peptide sequencing, and quantitation of phosphorylation by the introduction of mass tags (McLachlin and Chait 2001). 

Cantor RS. Lateral pressures in cell membranes a mechanism for modulation of protein function. J. Phys. Chem. 1997 101 1723-1725. 

The Challenge to Make Small-Molecule Modulators of Protein Function... 

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