Crystal structure of the potent natural product inhibitor balanol in complex with the catalytic subunit of cAMP-dependent protein kinase

Endogenous protein kinase inhibitors are essential for a wide range of phys iological functions. These endogenous inhibitors may mimic peptide substrat es as in the case of the heat-stable protein kinase inhibitor (PKI), or the y may mimic nucleotide triphosphates. Natural product inhibitors, endogenou s to the unique organisms producing them, can be potent exogenous inhibitor s against foreign protein kinases. Balanol is a natural product inhibitor e xhibiting low nanomolar K-i values against serine and threonine specific ki nases, while being ineffective against protein tyrosine kinases. To elucida te balanol's specific inhibitory effects and provide a basis for understand ing inhibition-regulated biological processes, a 2.1 Angstrom resolution cr ystal structure of balanol in complex with cAMP-dependent protein kinase (c APK) was determined. The structure reveals conserved binding regions and di splays extensive complementary interactions between balanol and conserved c APK residues. This report describes the structure of a protein kinase cryst allized with a natural ATP mimetic in the absence of metal ions and peptide inhibitor.