Enzyme‐mononucleotide interactions: Three different folds share common structural elements for atp recognition

Abstract

Three ATP-dependent enzymes with different folds, CAMP-dependent protein kinase, D-Ala:o-Ala ligase and the a-subunit of the a2P2 ribonucleotide reductase, have a similar organization of their ATP-binding sites. The most meaningful similarity was found over 23 structurally equivalent residues in each protein and includes three strands each from their @sheets, in addition to a connecting loop. The equivalent secondary structure elements in each of these enzymes donate four amino acids forming key hydrogen bonds responsible for the common orientation of the "AMP" moieties of their ATP-ligands. One lysine residue conserved throughout the three families binds the alpha-phosphate in each protein. The common fragments of structure also position some, but not all, of the equivalent residues involved in hydrophobic contacts with the adenine ring. These examples of convergent evolution reinforce the view that different proteins can fold in different ways to produce similar structures locally, and nature can take advantage of these features when structure and function demand it, as shown here for the common mode of ATP-binding by three unrelated proteins.Keywords: allosteric effector-binding site; ATP-dependent enzymes; convergent structural similarities; local structural comparisons; similar ligand-binding sites Adenosine 5"triphosphate (ATP) is necessary for the function of a wide variety of enzymes. Currently, the Brookhaven Protein Data Bank (PDB) (Bernstein et al., 1977) contains atomic coordinates for over 140 X-ray and NMR structures of ATP-dependent proteins solved as complexes mainly with bound ATP-analogues, bound AMP, bound ADP, and in some cases with bound ATP.Several distinct classes of folds of ATP-dependent enzymes have been identified (Schulz, 1992). Acharacteristic feature of these folds is the presence of a P-sheet, parallel or antiparallel, in the vicinity of the ATP-binding site. One class of folds, the classic mononucleotide-binding fold (Schulz & Schirmer, 1974;Rossmann et al., 1975;Schulz et al., 1986), has an ATP-binding site placed at the edge of a parallel P-sheet. Two other classes of folds, the protein kinase family fold (Hanks et al

Comparison of protein active site structures for functional annotation of proteins and drug design

“…45,51,52 Again, this lack of a strong evolutionary relationship between the various ATP binding proteins is consistent with the relatively low off-diagonal similarity scores observed in the CPASS analysis.…”

Finding local structural similarities among families of unrelated protein structures: A generic non-linear alignment algorithm

“…This was found every time when the set of C␣-atoms compared was limited to within a 15 Å or 20 Å radius sphere (five runs each). Unlike the case of DAla:DAla ligase (1IOW) and ribonucleotide reductase (3R1R) where the superposition with 1CDK revealed extensive structural similarities including the residue interactions responsible for the similar conformations of their bound cofactors, 3,40 in the case of 1LGR and 1CDK the similarities are less striking although the cofactors do overlap in space (Fig. 8C).…”

“…In addition, we have also applied GENFIT to find local similarities among enzymes with dissimilar folds: ATP-binding proteins 3,40 and pyridoxal phosphate binding proteins. 41 …”

LigAlign: Flexible ligand-based active site alignment and analysis

“…For example, the numbers next to the atoms depict the minimal bond distance from atom A. The topology vector for B is [3,5,1] indicating three atoms at distance 1, five atoms at distance 2, and one atom at distance 3.…”

“…Unfortunately, the non-local geometric constraints imposed by a global alignment will often prevent the discovery of locally conserved active site structure. This behavior is undesirable in the context of studying protein-ligand binding as active sites are often more conserved than the global protein shape [1,2]. One solution is to restrict alignment to the active site which induces a local alignment and reveals functionally relevant conserved structures.…”