title: The 1.76 A resolution crystal structure of glycogen phosphorylase B complexed with glucose, and CP320626, a potential antidiabetic drug.
abstract: CP320626, a potential antidiabetic drug, inhibits glycogen phosphorylase in synergism with glucose. To elucidate the structural basis of synergistic inhibition, we determined the structure of muscle glycogen phosphorylase b (MGPb) complexed with both glucose and CP320626 at 1.76 A resolution, and refined to a crystallographic R value of 0.211 (R(free)=0.235). CP320626 binds at a novel allosteric site, which is some 33 A from the catalytic site, where glucose binds. The high resolution structure allows unambiguous definition of the conformation of the 1-acetyl-4-hydroxy-piperidine ring supported by theoretical energy calculations. Both CP320626 and glucose promote the less active T-state, thereby explaining their synergistic inhibition. Structural comparison of MGPb--glucose--CP320626 complex with liver glycogen phosphorylase a (LGPa) complexed with a related compound (CP403700) show that the ligand binding site is conserved in LGPa.
authors.affiliation: Institute of Biological Research and Biotechnology, The National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, Athens 11635, Greece. ngo@eie.gr
authors.forename: Nikos G
authors.initials: NG
authors.lastname: Oikonomakos
authors.forename: Spyros E
authors.initials: SE
authors.lastname: Zographos
authors.forename: Vicky T
authors.initials: VT
authors.lastname: Skamnaki
authors.forename: Georgios
authors.initials: G
authors.lastname: Archontis
mesh_terms: D000495:Allosteric Site; D000577:Amides / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry; D005947:Glucose / Q000737:chemistry* / Q000378:metabolism; D024982:Glycogen Phosphorylase, Muscle Form / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry*; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007211:Indoles; D024982:Glycogen Phosphorylase, Muscle Form; C412544:CP 320626; D005947:Glucose