Dimerization Systems Homodimerization

In addition to FKBP-based systems, homodimerization has also been achieved using the naturally dimeric natural product coumermycin, which can dimerize proteins fused to Escherichia coli DNA gyrase [12]. 

Fig. 4.2-7 Comparison of conventional and proteins, (b) Reverse dimerization system "reverse FKBP dimerization systems. using monomeric ligand (AP21998) and (a) Induced dimerization using bumped F36M fusion proteins, homodimerizer AP20187 and F36V fusion...

Hydrogen bond interactions between the NH2C(0)C02 anions in oxamate salts have been shown to be dependent on the nature of the cations, with Rj(S) and 2(10) motifs between like faces and Rl(9) motifs between unlike faces all having been observed. In the two homodimeric systems, single hydrogen bonds link the dimers into tapes or sheets, whereas for the heterodimeric system, the 2(9) motifs lead directly to tapes [74]. 

The role of receptor homodimerization is more complicated than simply bringing the cytoplasmic elements of the receptors together. For example, structural studies of EPO and EPO-R indicate that a function of the hormone is to establish a fairly exact receptor alignment, as well as to induce dimerization (Livnah et al, 1998, 1999 Remy et al, 1999 Wilson and JoUiffe, 1999). Based on patterns of cross-hormone and cross-species activities and the known structural differences in the active complexes, exact receptor orientation is probably not as crucial for prolactin and growth hormone systems, although this has not been directly established. 

Chalcone and stilbene synthases are related plant PKSs [ 132]. Chalcones, such as naringenin chalcone, are produced as the biosynthetic precursors of flavinoids, while stilbenes are produced for their antifungal properties. Plant PKSs are likely to have evolved independendy from any of the aforementioned PKS and FAS systems [133, 134] and are atypical in many respects. These homodimeric enzymes consist of a single 40 kDa gene product (Fig. 2) [135]. The two active sites of the dimer function independently of one another [136]. Plant PKSs lack an AGP component, are not phosphopantetheinlyated, and act direcdy on CoA thioesters [134,137]. 

A rationally designed antiparallel, homodimeric a-helical coiled coil peptide served as a model system for the first systematic approach to investigating the interaction characteristics of fluorinated amino acids with native residues (Figure 15.2). The hydrophobic core of the model is exclusively composed of leucine, whereas complementary coulomb interactions between positions e and e as well as g and g control the antiparallel alignment of the helices within the dimer [25], In both strands, position a9 in the hydrophobic core... 

Fig. 4.2-3 Engineering specificity into FKBP dimerizing agents using "bumps and holes , (a) Homodimerization system. Bumped homodimers are able to induce dimers between FKBP fusion proteins engineered with appropriate holes , while evading endogenous FKBP.

The SDEL algorithm has also been applied to more complicated systems, such as the wild type human Cu, Zn superoxide dismutase (SOD) dimer. SOD is a 153-residue, homodimeric, anti-oxidant enzyme that dismutates superoxide ion to hydrogen peroxide and oxygen [87]. It is an eight-strand, flattened, beta-barrel protein with one copper and one zinc ion per monomer [88]. There are over 100... 

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