1lwn: Difference between revisions
New page: left|200px<br /><applet load="1lwn" size="450" color="white" frame="true" align="right" spinBox="true" caption="1lwn, resolution 2.00Å" /> '''Crystal structure of... |
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[[Image:1lwn.gif|left|200px]]<br /><applet load="1lwn" size=" | [[Image:1lwn.gif|left|200px]]<br /><applet load="1lwn" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1lwn, resolution 2.00Å" /> | caption="1lwn, resolution 2.00Å" /> | ||
'''Crystal structure of rabbit muscle glycogen phosphorylase a in complex with a potential hypoglycaemic drug at 2.0 A resolution'''<br /> | '''Crystal structure of rabbit muscle glycogen phosphorylase a in complex with a potential hypoglycaemic drug at 2.0 A resolution'''<br /> | ||
==Overview== | ==Overview== | ||
CP320626 has been identified as a potent inhibitor, synergistic with | CP320626 has been identified as a potent inhibitor, synergistic with glucose, of human liver glycogen phosphorylase a (LGPa), a possible target for type 2 diabetes therapy. CP320626 is also a potent inhibitor of human muscle GPa. In order to elucidate the structural basis of the mechanism of CP320626 inhibition, the structures of T state rabbit muscle GPa (MGPa) in complex with glucose and in complex with both glucose and CP320626 were determined at 2.0 A resolution, and refined to crystallographic R values of 0.179 (R(free)=0.218) and 0.207 (R(free)=0.235), respectively. CP320626 binds at the new allosteric site, some 33 A from the catalytic site, where glucose binds. The binding of CP320626 to MGPa does not promote extensive conformational changes except for small shifts of the side chain atoms of residues R60, V64, and K191. Both CP320626 and glucose promote the less active T state, while structural comparisons of MGPa-glucose-CP320626 complex with LGPa complexed with a related compound (CP403700) and a glucose analogue inhibitor indicate that the residues of the new allosteric site, conserved in the two isozymes, show no significant differences in their positions. | ||
==About this Structure== | ==About this Structure== | ||
1LWN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus] with GLC and PLP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Phosphorylase Phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.1 2.4.1.1] Full crystallographic information is available from [http:// | 1LWN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus] with <scene name='pdbligand=GLC:'>GLC</scene> and <scene name='pdbligand=PLP:'>PLP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Phosphorylase Phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.1 2.4.1.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LWN OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Phosphorylase]] | [[Category: Phosphorylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Chrysina, E | [[Category: Chrysina, E D.]] | ||
[[Category: Kosmopoulou, M.]] | [[Category: Kosmopoulou, M.]] | ||
[[Category: Leonidas, D | [[Category: Leonidas, D D.]] | ||
[[Category: Oikonomakos, N | [[Category: Oikonomakos, N G.]] | ||
[[Category: GLC]] | [[Category: GLC]] | ||
[[Category: PLP]] | [[Category: PLP]] | ||
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[[Category: type 2 diabetes]] | [[Category: type 2 diabetes]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:49:10 2008'' | ||
Revision as of 14:49, 21 February 2008
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Crystal structure of rabbit muscle glycogen phosphorylase a in complex with a potential hypoglycaemic drug at 2.0 A resolution
OverviewOverview
CP320626 has been identified as a potent inhibitor, synergistic with glucose, of human liver glycogen phosphorylase a (LGPa), a possible target for type 2 diabetes therapy. CP320626 is also a potent inhibitor of human muscle GPa. In order to elucidate the structural basis of the mechanism of CP320626 inhibition, the structures of T state rabbit muscle GPa (MGPa) in complex with glucose and in complex with both glucose and CP320626 were determined at 2.0 A resolution, and refined to crystallographic R values of 0.179 (R(free)=0.218) and 0.207 (R(free)=0.235), respectively. CP320626 binds at the new allosteric site, some 33 A from the catalytic site, where glucose binds. The binding of CP320626 to MGPa does not promote extensive conformational changes except for small shifts of the side chain atoms of residues R60, V64, and K191. Both CP320626 and glucose promote the less active T state, while structural comparisons of MGPa-glucose-CP320626 complex with LGPa complexed with a related compound (CP403700) and a glucose analogue inhibitor indicate that the residues of the new allosteric site, conserved in the two isozymes, show no significant differences in their positions.
About this StructureAbout this Structure
1LWN is a Single protein structure of sequence from Oryctolagus cuniculus with and as ligands. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of rabbit muscle glycogen phosphorylase a in complex with a potential hypoglycaemic drug at 2.0 A resolution., Oikonomakos NG, Chrysina ED, Kosmopoulou MN, Leonidas DD, Biochim Biophys Acta. 2003 Apr 11;1647(1-2):325-32. PMID:12686153
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