Molecular recognition of the protein phosphatase 1 glycogen targeting subunit by glycogen phosphorylase.
Disrupting the interaction between glycogen phosphorylase and the glycogen targeting subunit (G(L)) of protein phosphatase 1 is emerging as a novel target for the treatment of type 2 diabetes. To elucidate the molecular basis of binding, we have determined the crystal structure of liver phosphorylase bound to a G(L)-derived peptide. The structure reveals the C terminus of G(L) binding in a hydrophobically collapsed conformation to the allosteric regulator-binding site at the phosphorylase dimer interface. G(L) mimics interactions that are otherwise employed by the activator AMP. Functional studies show that G(L) binds tighter than AMP and confirm that the C-terminal Tyr-Tyr motif is the major determinant for G(L) binding potency. Our study validates the G(L)-phosphorylase interface as a novel target for small molecule interaction.
Pautsch
Alexander
A
Department of Lead Discovery, Boehringer Ingelheim GmbH & Co. KG, Birkendorferstrasse 65, Biberach, Germany. alexander.pautsch@boehringer-ingelheim.com
Stadler
Nadja
N
Wissdorf
Oliver
O
Langkopf
Elke
E
Moreth
Werner
W
Streicher
Rüdiger
R
D000249:Adenosine Monophosphate / Q000737:chemistry / Q000378:metabolism; D020816:Amino Acid Motifs / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D019281:Dimerization; D025001:Glycogen Phosphorylase, Liver Form / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000737:chemistry* / Q000378:metabolism; D020836:Protein Structure, Quaternary / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism
D010455:Peptides; D021122:Protein Subunits; D000249:Adenosine Monophosphate; D025001:Glycogen Phosphorylase, Liver Form; D054645:Protein Phosphatase 1