Ligand-induced conformational changes

Van Aalten, D.M.F., Findlay, J.B.C., Amadei, A., Berendsen,H.J.C. Essential dynamics of the cellular retinol-binding protein. Evidence for ligand-induced conformational changes. Protein Engin. 8 (1995) 1129-1136. 

The elegant genetic studies by the group of Charles Yanofsky at Stanford University, conducted before the crystal structure was known, confirm this mechanism. The side chain of Ala 77, which is in the loop region of the helix-turn-helix motif, faces the cavity where tryptophan binds. When this side chain is replaced by the bulkier side chain of Val, the mutant repressor does not require tryptophan to be able to bind specifically to the operator DNA. The presence of a bulkier valine side chain at position 77 maintains the heads in an active conformation even in the absence of bound tryptophan. The crystal structure of this mutant repressor, in the absence of tryptophan, is basically the same as that of the wild-type repressor with tryptophan. This is an excellent example of how ligand-induced conformational changes can be mimicked by amino acid substitutions in the protein. 

Ma, J.P. Karplus, M., Ligand-induced conformational changes in ras p21 a normal mode and energy minimization analysis, 7. Mol. Biol. 1997, 274,114—131... 

Characterization of ligand-induced conformational changes in atomic detail has primarily been studied through comparison of high-resolution X-ray structures for macromolecules crystallized in both free and ligand-bound states. The possibility of monitoring such... 

Frimurer TM, Peters GH, Iversen LF, Andersen HS, Moller NP, et al. 2003. Ligand-induced conformational changes improved predictions of ligand binding conformations and affinities. Biophys J 84(4) 2273-2281. 

We have completed several structures each of NPl, NP2, and NP4 (31, 46 9, 110). These structures reveal the Rhodnius nitrophorins to have a fold dominated by an eight-stranded antiparallel beta-barrel, as shown in Fig. 15, and to rely on a remarkable ligand-induced conformational change for NO transport, described later. The structures confirm that the nitrophorins are completely unrelated to the globins, the only other heme-based gas transport proteins whose structures are known. Rather, their fold places them in the lipocalin family, for which several other examples are known (111-113). Our initial nitrophorin structure was of NPl and was determined using standard MIR and... 

Computer-based techniques for locating and analyzing ligand binding sites on macromolecules. These methods must take into account the steric and electrostatic properties of ligand and receptor as well as ligand-induced conformational changes. 

Slow transitions produced by enzyme isomerizations. This behavior can lead to a type of cooperativity that is generally associated with ligand-induced conformational changes . A number of enzymes are also known to undergo slow oligomerization reactions, and these enzymes may display unusual kinetic properties. If this is observed, it is advisable to determine the time course of enzyme activation or inactivation following enzyme dilution. See Cooperativity Bifurcation Theory Lag Time... 

The original concept offered to explain why enzymes exhibit such a high degree of substrate specificity. The active site of an enzyme was viewed as a topological template for a particular reactant hence, there is an enzyme-substrate complementarity . See Induced-Fit Model Ligand-Induced Conformational Change E. Fischer (1894) Ber. 27, 2985. 

Ligand Binding Cooperativity Koshland-Nemethy-Filmer Model Scatchard Equation Ligand-Induced Conformational Change... 

ISOTOPE TRAPPING STICKY SUBSTRATES LIGAND EXCLUSION MODEL LIGAND FIELD SPLITTING CRYSTAL FIELD SPLITTING LIGAND-INDUCED CONFORMATIONAL CHANGE... 

INDUCED-FIT MODEL LIGAND-INDUCED CONFORMATIONAL CHANGE... 

The concept of control of metabolic activity by allosteric enzymes or the control of enzyme activity by ligand-induced conformational changes arose from the study of metabolic pathways and their regulatory enzymes. A good example is the multi-enzymatic sequence catalysing the conversion of L-threonine to L-isoleucine shown in Fig. 5.32. 

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