Reply: A polymerase I palm in adenylyl cyclase?

Bryant et al. reply — The adenylyl cyclase fold is a complex three-layer arrangement of α and β structures1 unlike any in the Brookhaven Protein Data Bank. Two simple and widely distributed motifs, the α/β roll11 and the double split βαβ (βαββαβ) sandwich11,12, occur as substructures (Fig. 2). The α/β roll comprises part of the inner two layers and the βαββαβ sandwich comprises part of the outer two layers. The substructures overlap, each forming part of the central β-sheet. The βαββαβ variant found in adenylyl cyclase has strand order 4-1-3-2, by far the most common12 (the third most common α+β structural motif in the Protein Data Bank11), occurring as a stand-alone domain structure in several nucleotide binding proteins and other unrelated proteins11,13. Figure 2 Homology model of C1and C2catalytic heterodimer of adenylyl cyclase, based on crystal structure of type-II C2homodimer. The seven-SSE region overlapping with DNA polymerase I is highlighted in yellow on the C1monomer and represents the βαββαβ substructure. The seven-SSE region overlapping with staphylococcal nuclease is highlighted in orange on the C2monomer and represents the β-barrel portion of the α/β roll substructure. Side-chains in the putative acidic cluster on type-I C1are in yellow (Asp 310, Asp 354 of type-I adenylyl cyclase; overlayable with polymerase) and red (Glu 432 of type I; unique to cyclases). Only one of the two forskolin molecules which bind the type-II C2homodimer is shown.