Conformational change on substrate binding

Mancia F, Evans PR (1998) Conformational changes on substrate binding to methylmalonyl CoA mutase and new insights into the free radical mechanism. Structure 6 711-720... 

The catalytic center of the protein tyrosine phosphatases includes ca. 230 amino acids and contains the conserved sequence motif H/V-C-(X)5-R-S/T-G/A/P (X is any amino acid), which is involved in phosphate binding and in catalysis. The available structural data on the catalytic domains of protein tyrosine phosphatases support the mechanism shown schematically in Fig. 8.20 (review Li and Dixon, 2000 Kolmodin and Aqvist, 2001). The invariant Cys and Arg residues of the P loop have a central function in binding and cleavage of the phosphate residue. Another catalytically important residue is an aspartic acid located in a loop distant from the active site cysteine. This loop undergoes a dramatic conformational change when substrate binds to the enzyme. 

Compared to most enzymes, which often undergo considerable conformational changes on binding of the substrates, hydrogenases are rather rigid proteins. The substrates are small and mobile, and can penetrate to the active site. Probably the only parts of the enzyme that move significantly are amino acid side-chains and bound water molecules involved in transfer of hydrons to the active site (Fig. 8.1). 

Structural studies of the oxy-Cope catalytic antibody system reinforce the idea that conformational dynamics of both protein and substrate are intimately intertwined with enzyme catalysis, and consideration of these dynamics is essential for complete understanding of biologically catalyzed reactions. Indeed, recent single molecule kinetic studies of enzyme-catalyzed reactions also suggest that different conformations of proteins are associated with different catalytic rates (Xie and Lu, 1999). In addition, a number of enzymes are known to undergo conformational changes on binding of substrate (Koshland, 1987) that lead to enhanced catalysis two examples are hexokinase (Anderson and Steitz, 1975 Dela-Fuente and Sols, 1970) and triosephosphate isomerase (Knowles, 1991). 

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