Fig. 7
From: Structural basis of human ABCC4 recognition of cAMP and ligand recognition flexibility

Flexible binding of cAMP to hABCC4. Information obtained from cryo-EM structural data revealed that the W995 residue plays a critical role in the binding of cAMP to hABCC4. Other potentially involved residues primarily contribute through hydrophobic interactions. However, these interactions are likely to have minimal effects on the binding of the hydrophilic cAMP molecule. As a result, cAMP is attracted and bound by W995 within the binding pocket. Owing to the lack of additional strong binding residues to stabilize it, the cAMP molecule undergoes flexible sliding. One of the rings of the cAMP molecule is closely aligned with the piperidine ring of W995 through π‒π stacking interactions. The remaining parts of the cAMP molecule undergo flexible sliding within a circular range centered around the piperidine ring. Regardless of the orientation in which cAMP is bound, the portion of the ligand near W995 consistently overlaps. This produces a disc-shaped, well-defined density, whereas the remaining parts fail to generate clear density