Enzyme binding site

We have already mentioned the application of supercomputers to biochemical simulations. Internal dynamics may play an Important role In such simulations. An example would be enzyme binding-site fluctuations that modulate reactivity or the dynamics of antigen-antibody association (11). In the specific case of diffusion-controlled processes, molecular recognition may occur because of long-range sterlc effects which are hard to assess without very expensive simulations (12.)-... 

Figure 12.7 Specific attachment of a prochiral centre to an enzyme-binding site enables the enzyme to distinguish between prochiral methylene protons in ethanol. (From Voet and Voet, 2004. Reproduced with permission from John Wiley Sons., Inc.)...

The 3D structures of several aminoglycoside-enzyme complexes have been described recently by X-ray methods [35,36]. Interestingly, in some cases, the 3D structure of the antibiotic in the enzyme binding site significantly... 

That this is not the case for the enzyme citrate synthase suggests we must look at the enzyme binding site to rationalize the different reaction sequence. It becomes clear that the enzyme binding site positions the substrates so that there are acidic and basic amino acid residues available to produce the enolate anion equivalent of acetyl-CoA (shown here as the enol), but not for the oxaloacetate (Figure 13.8). 

Recently a number of coreceptors containing two potential RNH3+ binding sites have been prepared, e.g. (19). These systems can complex either two alkylammonium cations (20) or one alkyldiammonium dication (21) inside the cavity (80TL941,81CC990,82CC557) and hold considerable potential as models of enzyme binding sites (Section 5.21.5.1.1). 

The ability of cyclic ethers to complex biologically important alkylammonium cations makes the choice of crown ethers as enzyme binding site models a natural one. In recent years a number of molecules containing both a crown ether-based substrate binding site and a potentially reactive group have been prepared as models for enzyme active sites (79PAC979, B-82MI52100). 

Bohacek, R. S., McMartin, C. (1994) Multiple highly diverse structures complementary to enzyme binding sites results of extensive application of a de novo design method incorporating combinatorial growth. J Am Chem Soc 116, 5560-5571. 

Recently, pharmacophores have been defined from homology models of CYP isoforms in the ALMOND program (Pastor et al., 2000). This method is based on an assessment of complementarity between binding properties of substrates and the enzymic binding sites. It assumes that within the enzyme-substrate complex, the site of reaction in the enzyme (the reactive oxygen atom) coincides... 

In the kinetic considerations discussed above, a plot of 1 /V0 vs 1/[S0] yields a straight line, and the enzyme exhibits Michaelis-Menten (hyperbolic or saturation) kinetics. It is implicit in this result that all the enzyme-binding sites have the same affinity for the substrate and operate independently of each other. However, many enzymes exist as oligomers containing subunits or domains that function in the regulation of the catalytic site. Such enzymes do not exhibit classic Michaelis-Menten saturation kinetics. 

RS Bohacek, C McMartin (1994) Multiple Highly Diverse Structures Complementary to Enzyme Binding Sites Results of Extensive Application of a de Novo Design Method Incorporating Combinatorial Growth, J Am Chem Soc 116(13) 5560-5571... 

The fraction of enzyme binding sites that are occupied is calculated... 

A dynamic combinatorial library of six components can be generated under thermodynamic control by imine formation and exchange combined with non-covalent bonding within the enzyme binding site and DCL was evaluated for their relative affinities toward the physiologically relevant human carbonic anhydrase hCA I and hCA II isozymes [66]. 

Breslow et al. (20) further expanded the use of cyclodextrin derivatives as models of enzyme-binding sites (these compounds are examples of the... 

The X-ray structures of vanadium bromoperoxidases from the red seaweeds Corallina pilulifera and C. officinalis have also been determined and their structures are almost identical. The native structure of these enzymes is dodecameric and the structure is made up of 6 homo-dimers. The secondary stmcture of the chloroperoxidase from the ftmgus Curvularia inaequalis that will be discussed later can be superimposed with the Corallina hromoperoxidase dimer. Many of the a helices of each chloroperoxidase domain are structurally equivalent to the a helices in the Corallina hromoperoxidase dimer. This is in line with the evolutionary relationship between the haloperoxidases that will be discussed later. The disulfide bridges in the enzyme from A. nodosum are not found in the enzyme from Corallina and the two remaining cysteine residues are not involved in disulfide bonds. Additionally, in this enzyme binding sites are present for divalent cations that seem to be necessary to maintain the stmcture of the active site cleft. All the residues directly involved in the binding of vanadate are conserved in the algal bromoperoxidases. ... 

RT/NNRTIs systems would be an exciting area of research for examining the particular interactions between the inhibitors and residues in the enzyme binding site. The information about such interactions will be beneficial for the design of appropriate inhibitors, in particular, active against mutant enzymes. 

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