抄録
X-ray crystallography is the potent tool for understanding the interactions between molecule and molecule. Here, I report the crystal structure of the complex between the protein phosphatase 1(PP1) catalytic subunit and its inhibitor, calyculin A, which shows direct evidence for understanding the general mechanism of the PP1 inhibition.
PP1 is one of the four major enzymes that dephosphorylate serine and threonine residues of proteins in the cytosol of eukaryotic cells. The catalytic subunit of PP1 (PP1c) is subjected to inhibition by various toxins such as okadaic acid, microcystin-LR (MCLR), calyculin A, and so on. X-ray crystallographic works of the PP1c complexed with MCLR or okadaic acid provided detailed views of the interaction between the enzyme and the toxins. Several binding models for calyculin A have been proposed on the basis of these crystal structures. However, calyculin A has very flexible backbone structure, and these models were purely speculative.
Calyculin A is located in two of the three grooves on the molecular surface in an extended form [1]. This is the first observation to note that the inhibitor adopts not a pseudocyclic conformation but an extended conformation in order to form a complex with the protein. The amino acid terminus of calyculin A contributes in a limited manner, to the binding to PP1c, which is consistent with findings from the studies of dose-inhibition analysis.
[1] Kita, A., Matsunaga, S., Takai, A., Kataiwa, H., Wakimoto, T., Fusetani, N., Isobe, M., Miki, K. (2002). Structure, 10, 715-724. [Jpn J Physiol 54 Suppl:S13 (2004)]
