Isoforms of Mammalian Adenylyl Cyclase: Multiplicities of Signaling

Structure of membrane-bound mammalian adenylyl cyclase bound to the activator Gα_s. (A) Illustration of the crystal structure of the catalytic domain of adenylyl cyclase bound to Gα_s (36) and superimposed onto the membrane-spanning region of mammalian adenylyl cyclase. Gα_s•GTPγ–S in its activated form is demarcated in gray. The cyclase domains, C1 (tan) and C2 (mauve) interact and form the binding sites for forskolin and the substrate, ATP. (B) The same structure as in (A) but rotated around the x-axis of vision to give a perspective from the inner surface of the membrane. Gα_i (in red) is overlaid onto the Gα_s•C1•C2 structure at the pseudosymmetrically related binding site to the Gα_s•GTPγ–S site. (C) The active site of adenylyl cyclase bound to the ATP analog ATPα–S(R_P). Highlighted are residues that make contact with the nucleotide and that are conserved in all mammalian adenylyl cyclases. Asp³⁹⁶ (D396), Asp⁴⁴⁰ (D440), and Arg⁴⁸⁴ (R484) are in the C1 domain of AC5. Lys⁹³⁸ (K938), Asp¹⁰¹⁸ (D1018), Arg¹⁰²⁹ (R1029), and Lys¹⁰⁶⁵ (K1065) are in the C2 domain of AC2. Also indicated are two Mg²⁺ ions liganded by the phosphates of ATPα‴S(R_P) and the two aspartate residues. The 3D structure was visualized with SwissPDBViewer™(178) and rendered with POV-RAY™ using coordinates from the Gα_s•C1•C2•forskolin•ATPα–S(R_P) (PDB id:1CJK) and Gα_i (PDB id:1GIA) structures.