in the catalytic cleft of the enzyme and participates in a salt bridge. Subfamilies Adenylate kinase, subfamily UMP-CMP kinase Adenylate kinase, isozyme 1 Mechanism Phosphoryl transfer only occurs on closing of the 'open lid'. This causes an exclusion of water molecules that brings the substrates in proximity to each other, lowering the energy barrier for the nucleophilic attack by the α-phosphoryl of AMP on the γ-phosphoryl group of ATP resulting in formation of ADP by transfer of the γ-phosphoryl group to AMP. In the crystal structure of the ADK enzyme from E. coli with inhibitor Ap5A, the Arg88 residue binds the Ap5A at the α-phosphate group. It has been shown that the mutation R88G results in 99% loss of catalytic activity of this enzyme, suggesting that this residue is intimately involved in the phosphoryl transfer. Another highly conserved residue is Arg119, which lies in the adenosine binding region of the ADK, and acts to sandwich the adenine in the active site. It has been suggested that the promiscuity of these enzymes in accepting other NTP's is due to this relatively inconsequential interactions of the base in the ATP binding pocket. A network of positive, conserved residues (Lys13, Arg123, Arg156, and Arg167 in ADK from E. coli) stabilize the buildup of negative charge on phosphoryl group during the transfer. Two distal aspartate residues bind to the arginine network, causing the enzyme to fold and reduces its flexibility. A magnesium cofactor is also required, essential for increasing the electrophilicity of the phosphate on AMP, though this magnesium ion is only held in the active pocket by electrostatic interactions and dissociates easily. Structure Flexibility and plasticity allow proteins to bind to ligands, form oligomers, aggregate, and perform mechanical work. Large conformational changes in proteins play an important role in cellular signaling. Adenylate Kinase is a signal transducing protein; thus, the balance between conformations regulates protein activity. ADK has a locally unfolded state that becomes depopulated upon binding. A 2007 study by Whitford et al. shows the conformations of ADK when binding with ATP or AMP. The study shows that there are three relevant conformations or structures of ADK—CORE, Open, and Closed. In ADK, there are two small domains called the LID and NMP. ATP binds in the pocket formed by the LID and CORE domains. AMP binds in the pocket formed by the NMP and CORE domains. The Whitford study also reported findings