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| | ==Crystal structure of Gpb in complex with 4a== | | ==Crystal structure of Gpb in complex with 4a== |
| - | <StructureSection load='4yi3' size='340' side='right' caption='[[4yi3]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4yi3' size='340' side='right'caption='[[4yi3]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4yi3]] 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=4YI3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YI3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4yi3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YI3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YI3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4D0:N-{[3-(BIPHENYL-4-YL)PROPANOYL]CARBAMOYL}-BETA-D-GLUCOPYRANOSYLAMINE'>4D0</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4D0:N-{[3-(BIPHENYL-4-YL)PROPANOYL]CARBAMOYL}-BETA-D-GLUCOPYRANOSYLAMINE'>4D0</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></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=4yi3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yi3 OCA], [http://pdbe.org/4yi3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yi3 RCSB], [http://www.ebi.ac.uk/pdbsum/4yi3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4yi3 ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4yi3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yi3 OCA], [https://pdbe.org/4yi3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yi3 RCSB], [https://www.ebi.ac.uk/pdbsum/4yi3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yi3 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PYGM_RABIT PYGM_RABIT]] Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. | + | [https://www.uniprot.org/uniprot/PYGM_RABIT PYGM_RABIT] Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4yi3" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4yi3" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Glycogen phosphorylase 3D structures|Glycogen phosphorylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | [[Category: Oryctolagus cuniculus]] | | [[Category: Oryctolagus cuniculus]] |
| - | [[Category: Phosphorylase]]
| + | [[Category: Chatzileontiadou DSM]] |
| - | [[Category: Chatzileontiadou, D S.M]] | + | [[Category: Kantsadi AL]] |
| - | [[Category: Kantsadi, A L]] | + | [[Category: Leonidas DD]] |
| - | [[Category: Leonidas, D D]] | + | [[Category: Stravodimos GA]] |
| - | [[Category: Stravodimos, G A]] | + | |
| - | [[Category: Alpha and beta protein]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
PYGM_RABIT Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties.
Publication Abstract from PubMed
Glycogen phosphorylase (GP), a validated target for the development of anti-hyperglycaemic agents, has been targeted for the design of novel glycopyranosylamine inhibitors. Exploiting the two most potent inhibitors from our previous study of N-acyl-beta-D-glucopyranosylamines (Parmenopoulou et al., Bioorg. Med. Chem. 2014, 22, 4810), we have extended the linking group to -NHCONHCO- between the glucose moiety and the aliphatic/aromatic substituent in the GP catalytic site beta-cavity. The N-acyl-N -(beta-D-glucopyranosyl) urea inhibitors were synthesized and their efficiency assessed by biochemical methods, revealing inhibition constant values of 4.95 microM and 2.53 microM. Crystal structures of GP in complex with these inhibitors were determined and analyzed, providing data for further structure based design efforts. A novel Linear Response - Molecular Mechanics Coulomb Surface Area (LR-MM-CBSA) method has been developed which relates predicted and experimental binding free energies for a training set of N-acyl-N -(beta-D-glucopyranosyl) urea ligands with a correlation coefficient R(2) of 0.89 and leave-one-out cross-validation (LOO-cv) Q(2) statistic of 0.79. The method has significant applications to direct future lead optimization studies, where ligand entropy loss on binding is revealed as a key factor to be considered. ADMET property predictions revealed that apart from potential permeability issues, the synthesized N-acyl-N -(beta-D-glucopyranosyl) urea inhibitors have drug-like potential without any toxicity warnings.
Glycogen phosphorylase as a target for type 2 diabetes: synthetic, biochemical, structural and computational evaluation of novel N-acyl-N -(beta-D-glucopyranosyl) urea inhibitors.,Kantsadi AL, Parmenopoulou V, Bakalov DN, Snelgrove L, Stravodimos GA, Chatzileontiadou DS, Manta S, Panagiotopoulou A, Hayes JM, Komiotis D, Leonidas DD Curr Top Med Chem. 2015;15(23):2373-89. PMID:26088352[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kantsadi AL, Parmenopoulou V, Bakalov DN, Snelgrove L, Stravodimos GA, Chatzileontiadou DS, Manta S, Panagiotopoulou A, Hayes JM, Komiotis D, Leonidas DD. Glycogen phosphorylase as a target for type 2 diabetes: synthetic, biochemical, structural and computational evaluation of novel N-acyl-N -(beta-D-glucopyranosyl) urea inhibitors. Curr Top Med Chem. 2015;15(23):2373-89. PMID:26088352
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