Allosteric cavity

Allosteric effect operates in a system exhibiting conformational mobility when inclusion of one guest creates an additional cavity for a second guest (Figure 2.2). A similar example with two identical guests was presented in Figure 1.6. 

Many systems are described in which changing the cavity shape by allosteric effects allows the cation binding ability and the selectivity of the receptor to be modified and controlled. For instance a photo-responsive cis/trans isomerizable azobenzene unit has been introduced in macrocyclic structures in order to change the receptors cavity shape, leading to a photo-control of ion extraction. 

Rhenium complexes 22a,b were designed as ditopic receptors for the cooperative complexation of ion pairs [21]. As proved by H NMR titration experiments in CD3CN,the receptors form complexes of 2 1 stoichiometry with alkali metal cations (interaction with both ethyl acetate cavities on the lower rim) and exhibit [16] a positive allosteric effect for iodide complexation compare... 

We tested whether the saccharide binding site on the upper rim could communicate with the metal binding site on the lower rim through the calix[4]arene cavity. The CD band weakened with increasing concentrations of Na+, Mg2+, or Ca2+. 78 On the other hand, when K+, Rb+, or Cs+ was added, the CD intensities increased and the spectral shape was changed. 78 For a number of reasons, we consider the new band to be attributable to the l,2-alternate-3- D-glucose-metal complexes. Therefore, this system is a unique example that exhibits both negative and positive allosteric interactions between metal ions and saccharides in a calix[4]arene host. 

H+, C02 and 2,3-bisphosphoglycerate are allosteric effectors, promoting the release of 02 from hemoglobin. H+ and C02 bind to different parts of the polypeptide chains, while 2,3-bisphosphoglycerate binds in the central cavity between the four subunits. 

Allosteric behavior in a ditopic cavitand receptor has been induced via metal coordination [62]. Addition of Ag+ ions to a solution of a 2,2 -bipyridine-bridged biscavitand 56 switches the molecule from an S-shaped to a C-shaped conformation with the two cavities facing each other. At the same time two bis-cavitand molecules are brought together to give an overall tetratopic complex 57 (Figure 7.24). 

Other approaches to self-assembling receptors have been reported in recent years. A self-assembling, trimeric palladium complex based on the bis(benzimidazole) ligand (17) was designed by Williams and coworkers [4]. The complex contains a hydrophobic cavity that in the X-ray structure has included a molecule of acetonitrile. In a different context, Schepartz and McDevitt [70] have used the chelation of nickel(n) by A,7V -bis(salicylaldehy-de)ethylenediamine (salen) derivatives to control the position of K -binding glyme chains, and it has been shown that these self-assembled ionophores influence alkali metal transport across liquid membranes [71]. Also, Shinkai and coworkers [72] and Schneider and Ruf [73] have used metal chelation to induce an allosteric effect on binding at a second site. 

In its most complete version, the Pocketome must be completed by likely cavities and allosteric pockets even if crystallo-graphically no small molecules have ever been observed in these cavities. We designed a pocket prediction algorithm based on a physical field, yet very general and relatively independent on the chemical nature of the ligand. This method, called ICM Pocket-Finder, performs the Gaussian convolution of the Lennard-Jones... 

Competitive inhibition of protein function is traditionally achieved at active sites using molecules that masquerade as enzyme substrates, or allosterically by small molecules that bind to cavities with recognition characteristics similar to active sites. It is not clear how to effectively inhibit PPIs with high affinity and selectivity using small molecules. In terms of competitive inhibition, a small molecule must... 

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