<p>(A) In the absence of CaM, the helical domain of EF (green rectangle) limits the accessibility of the catalytic core (orange rectangle), which contains the CaM-binding determinant (cyan ellipse). (B) When CaM (depicted by a pink sphere representing the N-terminal domain and a red sphere denoting the C-terminal domain) binds in the presence of 2β4 Ca<sup>2+</sup> ions (yellow spheres), the helical domain reorients, exposing the catalytic site (yellow star) of EF. (C) Surprisingly, two key structural elements of CyaA-ACD are disordered in the absence of CaM (gray and cyan traces), while the catalytic core (orange) is unstably folded (flexibility is depicted by wavy black outline). (D) CyaA-ACD, which lacks a helical domain, is inactive in the absence of CaM, presumably due to the lack of a stable catalytic site. In the presence of 4Ca<sup>2+</sup>-CaM, the domain involved in C-terminal CaM-binding (cyan ellipse) and another key region (gray ellipse with black arrow) become stably folded with increased rigidity. Furthermore, the catalytic core (orange rectangle with solid black line) is stabilized by CaM-binding and readily converts ATP to cAMP. ACT, adenylate cyclase toxin; ATP, adenosine triphosphate; CaM, calmodulin; cAMP, cyclic adenosine monophosphate; CyaA-ACD, adenylate cyclase domain of CyaA; EF, edema factor.</p