Crystal structure of the tumor-promoter okadaic acid bound to protein phosphatase-1

Protein phosphatase-1 (PP1) plays a key role in dephosphorylation in numero us biological processes such as glycogen metabolism, cell cycle regulation, smooth muscle contract-ion, and protein synthesis. Microorganisms produce a variety of inhibitors of PP1, which include the microcystin class of inhi bitors and okadaic acid, the latter being the major cause of diarrhetic she llfish poisoning and a powerful tumor promoter. We have determined the crys tal structure of the molecular complex of okadaic acid bound to PPI to a re solution of 1.9 Angstrom. This structure reveals that the acid binds in a h ydrophobic groove adjacent to the active site of the protein and interacts with basic residues within the active site. Okadaic acid exhibits a cyclic structure, which is maintained via an intramolecular hydrogen bond. This is reminiscent of other macrocyclic protein phosphatase inhibitors. The inhib itor-bound enzyme shows very little conformational change when compared wit h two other PPI structures, except in the inhibitor-sensitive beta 12-beta 13 loop region. The selectivity of okadaic acid for protein phosphatases-1 and -2A but not PP-2B (calcineurin) may be reassessed in light of this stud y.