Mechanisms induced fit, 115

Living cells contain thousands of different kinds of catalysts, each of which is necessary to life. Many of these catalysts are proteins called enzymes, large molecules with a slotlike active site, where reaction takes place (Fig. 13.39). The substrate, the molecule on which the enzyme acts, fits into the slot as a key fits into a lock (Fig. 13.40). However, unlike an ordinary lock, a protein molecule distorts slightly as the substrate molecule approaches, and its ability to undergo the correct distortion also determines whether the key will fit. This refinement of the original lock-and-key model is known as the induced-fit mechanism of enzyme action. 

Another difficulty is that a peptide may be able to bind to an existing neutralizing monoclonal antibody by an induced-fit mechanism that is somehow driven by the pre-existing structure of the antibody paratope. However, the same induced-fit process may not take place when the peptide is used as the immunogen and is confronted in the host by a large population of B cell receptors allowing a variety of other interactions. 

Connon and co-workers [137,147] also set out to develop a chiral catalyst which operates via an induced-fit mechanism. Derived from a 3-substituted 4-PPY and possessing a pendant aromatic group, this new catalyst (41, Fig. 7) allowed moderate to good selectivities to be achieved for a wide range of aryl alkyl i cc-alcohols. Connon [148] later showed that small improvements in selectivity could be obtained by introducing electron-deficient aryl groups. Finally, he was able to expand the substrate scope to include ec-alcohols obtained by Baylis-Hilhnan reaction [148]. 

The x-ray structure for yeast hexokinase is also available. Thus, glucose analogs are now being used to elucidate minute details of the catalytic mechanism. Recently D- lose was used in crystallographic work to show that the 6-hydro ethyl group of the natural substrate is necessary for substrate-induced closure of the active-site cleft (81 ). This induced closure, which is observed with glucose binding (82), is believed to be a part of the induced fit mechanism postulated for hexokinase (83) ... 

The hydrophobic cavity provided by the octopus cyclophane is significantly flexible, and capable of performing molecular recognition toward hydrophobic guest molecules of various bulkiness through the induced-fit mechanism, not only in aqueous solution but in the bilayer membrane formed with a synthetic peptide lipid. However, such a flexible hydrophobic cavity seems to be unfavorable for size-sensitive molecular discrimination. 

If Kbx/ Kax is very large, an insignificant amount of AX will be present at equilibrium. In such a case there is no way experimentally to determine KAX. The two constants Kt and KBX are sufficient to describe the equilibria but an induced fit mechanism may still hold. 

Del Carmine, R., Molinari, P., Sbraccia, M., Ambrosio, C., and Costa, T. (2004). Induced-fit mechanism for catecholamine binding to the beta2-adrenergic... 

Moores, C. A., Keep, N. H., and Kendrickjones, J. (2000b). Structure of the utrophin actin-binding domain bound to F-actin reveals binding by an induced fit mechanism./. Mol. Biol. 297, 465-480. 

Sawaya, M. R., Prasad, R., Wilson, S. H., Kraut, J., and Pelletier, H. (1997). Crystal structures of human DNA polymerase [S complexed with gapped and nicked DNA Evidence for an induced fit mechanism. Biochemistry 36, 11205-11215. 

Washington, M. T., Prakash, L., and Prakash, S. (2001). Yeast DNA polymerase y utilizes an induced-fit mechanism of nucleotide incorporation. Cell 107, 917-927. 

Loo TW, Bartlett MC, Clarke DM. Substrate-induced conformational changes in the transmembrane segments of human P-glycoprotein. Direct evidence for the substrate-induced fit mechanism for drug binding. J Biol Chem 2003 278 13603-13606. 

Box 18.2. Schematic Description of the Induced Fit Mechanism of a-Cyclodextrin Inclusion Formation... 

A completely different approach was pursued by Fuji and coworkers [14]. The enantiomeri-cally pure pyridine derivative 18 was prepared, the rationale being that the reduced steric hindrance in the proximity of the nitrogen nucleus should result in efficient catalytic turnover and that chiral recognition might be possible by remote asymmetric induction in a process similar to the induced fit mechanism in enzymes. When 18 was reacted with racemic 19b and isobutyric anhydride (l/ ,25)-19b was recovered with ee = 81% (71% conversion, 5 = 4.5,... 

Enzymes are biological catalysts whose role is to increase the rate of chemical (metabolic) reactions without being consumed in the reaction. They do so by lowering the activation energy of a reaction by binding specifically (i.e., in the active site) to their substrates in a lock-and-key or induced-fit mechanism. They do not change the nature of the reaction (in fact, any... 

However, a number of biological findings could not be explained by the CPCA analysis. The authors attribute this to the fact that the ephrin-Eph kinase interactions are best described by an induced fit mechanism. The necessary computational assumption of keeping the protein structure rigid did not reflect the flexibility of the protein interfaces and their structural adaptability. The homology models, on the other hand, provided a rigid protein structure that is biased by the template protein EphB2. 

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