Protein allosteric

The influence of solvent can be incorporated in an implicit fashion to yield so-called langevin modes. Although NMA has been applied to allosteric proteins previously, the predictive power of normal mode analysis is intrinsically limited to the regime of fast structural fluctuations. Slow conformational transitions are dominantly found in the regime of anharmonic protein motion. 

Steitz, T.A., et al. High resolution x-ray structure of yeast hexokinase, an allosteric protein exhibiting a non-symmetric arrangement of subunits. 

Effector molecules switch allosteric proteins between R and T states... 

For many years hemoglobin was the only allosteric protein whose stereochemical mechanism was understood in detail. However, more recently detailed structural information has been obtained for both the R and the T states of several enzymes as well as one genetic repressor system, the trp-repressor, described in Chapter 8. We will here examine the structural differences between the R and the T states of a key enzyme in the glycolytic pathway, phosphofructokinase. 

In 1965, Jacques Monod, Jeffries Wyman, and Jean-Pierre Changeux proposed a theoretical model of allosteric transitions based on the observation that allosteric proteins are oligomers. They suggested that allosteric proteins can exist in (at least) two conformational states, designated R, signifying relaxed, and T, or taut, and that, in each protein molecule, all of the subunits have the same conformation (either R or T). That is, molecular symmetry is conserved. Molecules of mixed conformation (having subunits of both R and T states) are not allowed by this model. 

In the absence of ligand, the two states of the allosteric protein are in equilibrium ... 

The properties of individual hemoglobins are consequences of their quaternary as well as of their secondary and tertiary structures. The quaternary structure of hemoglobin confers striking additional properties, absent from monomeric myoglobin, which adapts it to its unique biologic roles. The allosteric (Gk alios other, steros space ) properties of hemoglobin provide, in addition, a model for understanding other allosteric proteins (see Chapter 11). 

Changeux, JP (1990) The nicotinic acetylcholine receptor an allosteric protein protot5q)e of ligand-gated ion channels. Trends Pharmacol. Sci. 11 485M92. 

Monod J, Changeux J-P, Jacob F. Allosteric proteins and cellular control systems. J Mol Biol 1963 6 308-329. 

Changeux, J. P., Devillers-Thiery, A Chemouilli, P. (1984). Acetylcholine receptor an allosteric protein. Science 225, 1335-45. 

Galzi, J. L. and Changeux, J. P. (1994) Neurotransmitter-gated ion channel as unconventional allosteric proteins. Curr. Opin. Struct. Biol. 4, 554-565. 

Not all allosteric proteins are enzymes. In fact, probably the best-known and characterized allosteric protein is haemoglobin, which like an enzyme binds ligands (small molecules) to itself, for example, oxygen rather than a substrate. 

Haemoglobin is one of the most well studied and best understood proteins thanks largely to the early work of Max Perutz, John Kendrew and colleagues. Haemoglobin is now often used as a model allosteric protein and to illustrate the impact of protein structural alterations in disease. 

On the other hand, small start-up companies focused intensely and entirely on what they were created to do, with the incentive that early and even later employees would be well rewarded if the venture was successful. It was clear to me, in this case, that if the translation from basic and preclinical research to clinical trials were to occur, our best chance was to initiate a company. For the most part, big pharmaceutical houses have stayed clear of allosteric effectors as drugs. We had the enormous advantage that far more is known about hemoglobin as an allosteric protein than any other. 

Alpha particle Electric polarizability Reduced concentration ([F]/Xf) for allosteric protein... 

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