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X-Ray Structure of Balanol (PDB-code 1BX6)

The complex of the natural (-)-balanol with PKA (PDB-code 1BX6) was solved in 1999 (Narayana et al. 1999). The molecule (Fig. 7) can be considered in terms of occupation of three regions of the ATP binding pocket: a phenol (Fig. 7, ring A) in the adenine subsite, an azepane (B) in the ribose subsite and the benzophenone (C and D) occupies the triphosphate subsite.

The phenol makes two H-bonds from the -OH group to the hinge region Val123(N) and Glu121(0); VDW contacts exist to Leu49, Ala70, Glu121, Tyr122, Val123, Thr183 and Phe327. The amide that links to the azepane ring makes one H-bond to a water molecule with its amide nitrogen and to Thr183 with its carbonyl oxygen. The azepane ring is in VDW contact with Gly50, Glu127 and Glu170, and additionally forms an H-bond with Gly170. The benzophenone part interacts with Thr51, Gly52, Ser53, Phe54, Gly55, Arg56, Lys72, Leu74, Gln84, Glu91, Asp184, Gly186, Phe187. Benzophenone substituents are involved in several H-bonds: to Gly52, Ser53, Phe54, and

Fig. 7 Chemical structure of the natural (-)-balanol and the novel balanol derivatives. (Breitenlechner et al. 2004)

Gly55 from the glycine loop, to the conserved residues Lys72 and Glu91, and to Asp184 from the beginning of the activation loop.

In total, there are 21 H-bonds and 114 VDW interactions, whereas most occur with the triphosphate subsite (Narayana et al. 1999; Setyawan et al. 1999; Wong et al. 2001).

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