Nucleotide binding domain dehydrogenase

Several lines of evidence—sequence analysis, mutagenesis studies, and the solved 3D structure of homologs of 11P-HSD—indicate that the nucleotide binding site in these enzymes has many similarities to that in other classes of dehydrogenases. For many dehydrogenases, the nucleotide binding domain... 

RGURE 13-16 The nucleotide binding domain of the enzyme lactate dehydrogenase, (a) The Rossmann fold is a structural motif found in the NAD-binding site of many dehydrogenases It consists of a six-stranded parallel /3 sheet and four a helices inspection reveals the arrangement to be a pair of structurally similar motifs... 

Figure 2-13 (A) Stereoscopic view of the nucleotide binding domain of glyceraldehyde phosphate dehydrogenase. The enzyme is from Bacillus stearothermophilus but is homologous to the enzyme from animal sources. Residues are numbered 0-148. In this wire model all of the main chain C, O, and N atoms are shown but side chains have been omitted. The large central twisted P sheet, with strands roughly perpendicular to the page, is seen clearly hydrogen bonds are indicated by dashed lines. Helices are visible on both sides of the sheet. The coenzyme NAD+ is bound at the end of the P sheet toward the viewer. Note that the two phosphate groups in the center of the NAD+ are H-bonded to the N terminus of the helix beginning with RIO. From Skarzynski et al.llla (B) Structural formula for NAD+.

The structures of several dehydrogenases have now been solved. The work on these has been reviewed in depth in the literature, as have their physical and kinetic properties.1,9,10 Some generalizations can be made. As was discussed in Chapter 1, section D6, the subunits may be divided into two domains a catalytic domain, which can be quite variable in structure, and a nucleotide-binding domain, which is formed from a similar overall folding of the polypeptide chain for all the dehydrogenases. The detailed geometry of the nucleotide-binding... 

Twisted sheets. X-ray diffraction studies have shown that P pleated sheets are usually not flat but are twisted. In a twisted sheet the individual polypeptide chains make a shallow left-handed helix. However, when successive carbonyl groups are viewed along the direction of the chain, a rig t-handed twist is seen (Fig. 2-12). ° Such twisted P sheets are often found in the globular proteins. An example (Fig. 2-13) is the "nucleotide-binding" domain of a dehydrogenase enzyme. The twist of the sheet is seen clearly in this stereoscopic view. When such chains are associated into P sheets, whether parallel or antiparallel, and are viewed in a direction perpendicular to the chains and looking down the edge of the sheet, a left-handed "propeller" is seen. Such a propeller is visible in the... 

The nucleotides NAD, NADH, FAD, and FMN are all known to be inhibitors. The structure of this enzyme was solved (74) and was found to have two repeating structural domains along a (probably) single polypeptide chain. Each domain contained a fold reminiscent of the nucleotide binding domains in the dehydrogenases. It remains to be seen whether nucleotides bind in a manner suggested by the structural similarity. 

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