Rossmann fold domain

In each of the three divisions of life, the most common fold is the P-loop NTPase. Four common folds, namely P-loop NTPases, Triose Phosphate Isomerase (TIM) barrels, ferredoxin-like domains, and Rossmann-fold domains, are see in the top-10 lists for all three divisions (Table IV). 

A more detailed breakdown of the fold abundance by individual genomes shows the same trends, as well as a number of unique features (Fig. 6, see color insert). The latter include, for example, the marked overrepresentation of Rossmann-fold domains in Mycobacterium, flavo-doxins in Synechocystis and methyltransferases in Helicobacter. Furthermore, the differences in fold distribution between the multicellular eukaryote Caenorhabditis elegans and the unicellular yeast become readily apparent. In the nematode, the protein kinases are the most common fold, with the P-loops relegated to the second position in contrast, the yeast distribution is more similar to that seen in prokaryotes (Fig. 6). 

NAD(P)-binding Rossmann-fold domains NAD(P)-binding Rossmann-fold domains Alcohol/glucose dehydrogenases, carboxyl-terminal domain Alcohol dehydrogenase Human Homo sapiens)... 

The overall fold of MIPS is similar to that of diaminopimelic acid dehydrogenase from Corynebacterium glutamicum and dihydrodipicolinate reductase from E. coli. Though the reactions catalyzed by these enzymes are quite different, they all use either NAD+ or NADP+ bound to a structurally similar Rossmann fold domain, and all three contain a (3 sheet domain located underneath the Rossmann fold and directly beneath the nicotinamide moiety that defines part of the active site (Norman et al., 2002 Stein and Geiger, 2002). 

The active site of MIPS is located between the bottom of the Rossmann fold domain and the (3 sheet of the catalytic domain. Two helices, a 14 and al5 stretch across the front of the active site and al3 forms the side of the active site. NAD+ forms the top of the active site with the adenine ring more or less centered in the active site cavity. Numerous structures of MIPS have been determined and shed considerable light on the mechanism of the enzyme. Generally, the active site is characterized by a great deal of flexibility. This is particularly true of yMIPS. 

Fig. 2. Three-dimensional structure of M. tuberculosis dihydropicolinate reductase consisting of the Rossmann-fold domain with bound NAD (stick representation and the catalytic domain with bound the substrate pyridine-2,6-dicarboxylic acid (stick representation (100).

The class III deacetylases, named sirtuins, are structurally and functionally different from other HDACs. In contrast to the zinc-dependent deacetylation of classic HDACs, sirtuins depend on NAD" to carry out catalytic reactions. A variety of sirtuin crystal structures have been published over the past few years. The structures of human Sirt2 and SirtS as well as several bacterial Sir2 proteins could be derived, whereas no 3D structure is available for Sirtl and the other subtypes [69]. All solved sirtuin structures contain a conserved 270-amino-acid catalytic domain with variable N- and C-termini. The structure of the catalytic domain consists of a large classic Rossmann fold and a small zinc binding domain. The interface between the large and the small subdomain is commonly subdivided into A, B and C pockets. This division is based on the interaction of adenine (A), ribose (B) and nicotinamide (C) which are parts of the NAD" cofactor. (Figure 3.5) Whereas the interaction of adenine and... 

Figure 2. Pharmacofamilies of the NADH cofactor (structure shown in panel A) binding to oxi-doreductases. Panel B shows an overlay of a subset of NAD(P)(H) geometries obtained from 288 crystal structures of oxidoreductases. The two largest pharmacofamilies are shown, corresponding to the two-domain Rossmann fold enzymes in pharmacofamilies 1 (anti) and 2 (syn). Panel C shows the corresponding pharmacophores with all protein heteroatoms indicated that are within hydrogen bonding distance of atoms in the cofactor. (Figure adapted with permission from original work of Sem ef o/. ).

Most dehydrogenases that use NAD or NADP bind the cofactor in a conserved protein domain called the Rossmann fold (named for Mchael Rossmann, who deduced the structure of lactate dehydrogenase and first described this structural motif). The Rossmann fold typically consists of a six-stranded parallel /3 sheet and four associated a helices (Fig. 13-16). 

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... 

Rocky Mountain spotted fever 7 Rods (visual receptor cells) 390 Root hairs, dimensions of 30 Roseoflavin 788, 789s Rossmann fold. See Nucleotide-binding domain Rotamases 488 Rotary diffusion constant 463 Rotation of molecules 462,463 Rotational barrier 44 Rotifers 24, 25... 

Reitzer et al., 1999) and a MeCbl-binding fragment of E. coli methionine synthase (Drennan et al., 1994), the cofactor is sandwiched between two domains (Figure 8). The conserved domain possesses an a/ 3 structure reminiscent of the Rossmann fold of nucleotide-binding proteins (Rossmann et al., 1974) and consists of a twisted )-sheet of five parallel strands encased by five a-helices. It binds the lower, a-face of the corrin macrocycle and the substituents projecting idowni from this face, notably the dimethylbenz-imidazole ribofuranosyl nucleotide loop. 

Figure 17.14. Structure of Succinyl CoA Synthetase. The enzyme is composed of two subunits. The a subunit contains a Rossmann fold that binds the ADP component of CoA, and the (3 subunit contains a nucleotideactivating region called the ATP-grasp domain. The ATP-grasp domain is shown here binding a molecule of ADP. The histidine residue picks up the phosphoryl group from near the CoA and swings over to transfer it to the nucleotide bound in the ATP-grasp domain.

At least one aminoacyl-tRNA synthetase exists for each amino acid. The diverse sizes, subunit composition, and sequences of these enzymes vv ere be vildering for many years. Could it be that essentially all synthetases evolved independently The determination of the three-dimensional structures of several synthetases follo ved by more-refined sequence comparisons revealed that different synthetases are, in fact, related. Specifically, synthetases fall into tvv o classes, termed class I and class II, each of vv hich includes enzymes specific for 10 of the 20 amino acids (Table 29.2). Glutaminyl-tRNA synthetase is a representative of class I. The activation domain for class I has a Rossmann fold (Section 16.1.101. Threonyl-tRNA synthetase (see Figure 29.11) is a representative of class II. The activation domain for class II consists largely of P strands. Intriguingly, synthetases from the tvv o classes bind to different faces of the tRNA molecule (Figure 29.14). The CCA arm of tRNA adopts different conformations to accommodate these interactions the arm is in the helical conformation observed for free tRNA (see Figures 29.5 and 29.6) for class II enzymes and in a hairpin conformation for class I enzymes. These two classes also differ in other ways. 

This device should be common to all Fj s, and in fact these clusters are found in the homologous sequences in the subunits of MF], CF, and EFj. The acidic cluster is composed of Asp-Glu-Leu-Ser-Glu-Glu-Asp (residues no. 381-387 of EFj) and the basic cluster of Arg-Ala-Lys-Ile-X-Arg (no. 393-399) (Fig. 5.4) [31]. There are other small clusters which are also homologous in F/s, but the clusters mentioned above are located very close to the Rossmann fold, as shown in Fig. 5.6. There are a few clusters in subunits a and b, which may transfer energy of H" flux. The invariant Arg-41 of subunit c may become a candidate of the basic cluster if c subunits form an oligomer. Intracistronic mapping of the defective site of the 12y8 subunit mutants in the domain II (from residue no. 288 to the C-terminus) revealed that many of... 

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