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[[ | ==Glycogen Phosphorylase b in complex with 3 -C-(hydroxymethyl)-beta-D-glucopyranonucleoside of 5-fluorouracil== | ||
<StructureSection load='3sym' size='340' side='right' caption='[[3sym]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3sym]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SYM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SYM FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GP0:5-FLUORO-1-[3-C-(HYDROXYMETHYL)-BETA-D-GLUCOPYRANOSYL]PYRIMIDINE-2,4(1H,3H)-DIONE'>GP0</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=LLP:2-LYSINE(3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YLMETHANE)'>LLP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3syr|3syr]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3sym FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sym OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sym RCSB], [http://www.ebi.ac.uk/pdbsum/3sym PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Glycogen phosphorylase is a molecular target for the design of potential hypoglycaemic agents. Structure based design pinpointed that the 3'-position of glucopyranose equipped with a suitable group has the potential to form interactions with enzyme's cofactor, PLP, thus enhancing the inhibitory potency. Hence, we have investigated the binding of two ligands, 1-(beta-D-glucopyranosyl)5-fluorouracil (GlcFU) and its 3'-CH(2) OH glucopyranose derivative. Both ligands were found to be low muM inhibitors with K(i) values of 7.9 and 27.1 muM, respectively. X-ray crystallography revealed that the 3'-CH(2) OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP gamma-phosphate compared to GlcFU. However it is 3.4 times less potent. To elucidate this discovery, docking followed by post-docking Quantum Mechanics/Molecular Mechanics - Poisson Boltzmann Surface Area (QM/MM-PBSA) binding affinity calculations were performed. While the docking predictions failed to reflect the kinetic results, the QM/MM-PBSA revealed that the desolvation energy cost for binding of the 3'-CH(2) OH-substituted glucopyranose derivative out-weigh the enthalpy gains from the extra contacts formed. The benefits of performing post-docking calculations employing a more accurate solvation model and the QM/MM-PBSA methodology in lead optimization is therefore highlighted, specifically when the role of a highly polar/charged binding interface is significant. (c) 2012 John Wiley & Sons A/S. | |||
3'-axial CH(2) OH substitution on glucopyranose does not increase glycogen phosphorylase inhibitory potency. QM/MM-PBSA calculations suggest why.,Manta S, Xipnitou A, Kiritsis C, Kantsadi AL, Hayes JM, Skamnaki VT, Lamprakis C, Kontou M, Zoumpoulakis P, Zographos SE, Leonidas DD, Komiotis D Chem Biol Drug Des. 2012 Feb 2. doi: 10.1111/j.1747-0285.2012.01349.x. PMID:22296957<ref>PMID:22296957</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Glycogen Phosphorylase|Glycogen Phosphorylase]] | *[[Glycogen Phosphorylase|Glycogen Phosphorylase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Oryctolagus cuniculus]] | [[Category: Oryctolagus cuniculus]] | ||
[[Category: Phosphorylase]] | [[Category: Phosphorylase]] | ||
[[Category: Katsandi, A L | [[Category: Katsandi, A L]] | ||
[[Category: Kontou, M | [[Category: Kontou, M]] | ||
[[Category: Leonidas, D D | [[Category: Leonidas, D D]] | ||
[[Category: Skamnaki, V T | [[Category: Skamnaki, V T]] | ||
[[Category: Alpha and beta protein]] | [[Category: Alpha and beta protein]] | ||
[[Category: Glycogen metabolism]] | [[Category: Glycogen metabolism]] | ||