DNA polymerases are analogous. Both involve attack by the 3፱ OH group of a ribose unit on the Ȋ-phosphate of a nucleotide 5፱-triphosphate, with the elimination of pyrophosphate. However, in the polymerase reaction a deoxyribonucleotide is ligated to a DNA primer, whereas in adenylyl cyclase the reaction involves an intramolecular cyclization within one ATP molecule. The key catalytic residues in the polymerase I active site are three acidic groups (Asp 610, Asp 785 and Glu 786 in Taq polymerase) which bind Mg 2+ and are positioned at the top end of the palm region (Fig. 1a). Although two of the equivalent residues are usually aspartates (Asp 891 and 942) in the C 1 -region of ACYc, all three are hydroxyls in the C 2 -region reported by Zhang et al. 1 (Fig. 1b: Ser 891, which hydrogen-bonds to the highly conserved Arg 977;Ser 942 which interacts with forskolin at the dimer interface; and Thr 943).The ATP-binding site in ACYc is not known, but mutagenesis studies 1,8 show that residues from strand 4 and helix C are involved in ATP binding and catalysis. These residues are adjacent to the positions equivalent to the polymerase active site (Fig. 1a, b) on the same face of the ȋ-sheet, so it seems likely that nucleotide triphosphate will bind in a broadly similar position in both classes of enzyme. Differences in the active site sidechains are to be expected because, in the polymerase, base recognition is in part provided by the complementary template DNA strand. It would be surprising if the detailed chemistry of intra-and intermolecular elimination of pyrophosphate were identical.These molecules share the same unusual fold, their active sites seem to be in roughly scientific correspondence Figure 1 Chain traces 9, 10 of a, the palm domain of Taq polymerase (ref. 6; PDB code, 1TAQ) and b, a monomer of ACYc (ref. 1; PDB code, 1AB8). Equivalent helices and strands, shown as red coiled ribbons and sequentially numbered green arrows, respectively, occur in the same order in both structures. The additional strand and helix in the C terminus of ACYc are in blue. Other non-equivalent parts of the structures are shown as yellow smoothed CȊ traces, with dashes indicating disordered regions in ACYc. In the polymerase the thumb domain (not shown) is towards the N terminus of the palm domain, and the fingers domain is between strand 1 and helix A. Side chains implicated in the activity of both enzymes are shown in ball-andstick representation: a, left to right, Asp 785, Glu 786 and Asp 610; b, top to bottom on helix C and strand 4, Arg 977, Ser 1,032, Asp 1,031, Arg 1,029 and Asn 1,025. For ACYc, a forskolin molecule is shown above Ser 942, Thr 943 and Ser 891 (left to right). c, Stereo diagrams 9 showing the superposition of Ȋ-carbons of ACYc catalytic domain (blue) and the palm domain of Taq polymerase (yellow) in the same orientation as in a and b.