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| | == Structural highlights == | | == Structural highlights == |
| | <table><tr><td colspan='2'>[[1e1y]] 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=1E1Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1E1Y FirstGlance]. <br> | | <table><tr><td colspan='2'>[[1e1y]] 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=1E1Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1E1Y FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CPB:2-(2-CHLORO-PHENYL)-5,7-DIHYDROXY-8-(3-HYDROXY-1-METHYL-PIPERIDIN-4-YL)-4H-BENZOPYRAN-4-ONE'>CPB</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>, <scene name='pdbligand=PO3:PHOSPHITE+ION'>PO3</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]] 2.23Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1gpa|1gpa]], [[2gpa|2gpa]], [[1gpb|1gpb]], [[2gpb|2gpb]], [[3gpb|3gpb]], [[4gpb|4gpb]], [[5gpb|5gpb]], [[6gpb|6gpb]], [[7gpb|7gpb]], [[8gpb|8gpb]], [[9gpb|9gpb]], [[1abb|1abb]], [[1gpy|1gpy]], [[1noi|1noi]], [[1noj|1noj]], [[1nok|1nok]], [[1pyg|1pyg]], [[2pri|2pri]], [[2prj|2prj]], [[2amv|2amv]], [[3amv|3amv]], [[2skc|2skc]], [[2skd|2skd]], [[2ske|2ske]], [[1axr|1axr]], [[2gpn|2gpn]], [[1a8i|1a8i]], [[1bx3|1bx3]], [[1b4d|1b4d]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CPB:2-(2-CHLORO-PHENYL)-5,7-DIHYDROXY-8-(3-HYDROXY-1-METHYL-PIPERIDIN-4-YL)-4H-BENZOPYRAN-4-ONE'>CPB</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>, <scene name='pdbligand=PO3:PHOSPHITE+ION'>PO3</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Phosphorylase Phosphorylase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=1e1y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e1y OCA], [https://pdbe.org/1e1y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1e1y RCSB], [https://www.ebi.ac.uk/pdbsum/1e1y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1e1y 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=1e1y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e1y OCA], [https://pdbe.org/1e1y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1e1y RCSB], [https://www.ebi.ac.uk/pdbsum/1e1y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1e1y ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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.
| + | [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. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| | [[Category: Oryctolagus cuniculus]] | | [[Category: Oryctolagus cuniculus]] |
| - | [[Category: Phosphorylase]]
| + | [[Category: Johnson LN]] |
| - | [[Category: Johnson, L N]] | + | [[Category: Oikonomakos NG]] |
| - | [[Category: Oikonomakos, N G]] | + | [[Category: Skamnaki VT]] |
| - | [[Category: Skamnaki, V T]] | + | [[Category: Tsitsanou KE]] |
| - | [[Category: Tsitsanou, K E]] | + | [[Category: Zographos SE]] |
| - | [[Category: Zographos, S E]] | + | |
| - | [[Category: Allosteric inhibition]]
| + | |
| - | [[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.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Flavopiridol (L86-8275) ((-)-cis-5, 7-dihydroxy-2-(2-chlorophenyl)-8-[4-(3-hydroxy-1-methyl)-piperidinyl] -4H-benzopyran-4-one), a potential antitumor drug, currently in phase II trials, has been shown to be an inhibitor of muscle glycogen phosphorylase (GP) and to cause glycogen accumulation in A549 non-small cell lung carcinoma cells (Kaiser, A., Nishi, K., Gorin, F.A., Walsh, D.A., Bradbury, E. M., and Schnier, J. B., unpublished data). Kinetic experiments reported here show that flavopiridol inhibits GPb with an IC(50) = 15.5 microm. The inhibition is synergistic with glucose resulting in a reduction of IC(50) for flavopiridol to 2.3 microm and mimics the inhibition of caffeine. In order to elucidate the structural basis of inhibition, we determined the structures of GPb complexed with flavopiridol, GPb complexed with caffeine, and GPa complexed with both glucose and flavopiridol at 1.76-, 2.30-, and 2.23-A resolution, and refined to crystallographic R values of 0.216 (R(free) = 0.247), 0.189 (R(free) = 0.219), and 0.195 (R(free) = 0.252), respectively. The structures provide a rational for flavopiridol potency and synergism with glucose inhibitory action. Flavopiridol binds at the allosteric inhibitor site, situated at the entrance to the catalytic site, the site where caffeine binds. Flavopiridol intercalates between the two aromatic rings of Phe(285) and Tyr(613). Both flavopiridol and glucose promote the less active T-state through localization of the closed position of the 280s loop which blocks access to the catalytic site, thereby explaining their synergistic inhibition. The mode of interactions of flavopiridol with GP is different from that of des-chloro-flavopiridol with CDK2, illustrating how different functional parts of the inhibitor can be used to provide specific and potent binding to two different enzymes.
Flavopiridol inhibits glycogen phosphorylase by binding at the inhibitor site.,Oikonomakos NG, Schnier JB, Zographos SE, Skamnaki VT, Tsitsanou KE, Johnson LN J Biol Chem. 2000 Nov 3;275(44):34566-73. PMID:10924512[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Oikonomakos NG, Schnier JB, Zographos SE, Skamnaki VT, Tsitsanou KE, Johnson LN. Flavopiridol inhibits glycogen phosphorylase by binding at the inhibitor site. J Biol Chem. 2000 Nov 3;275(44):34566-73. PMID:10924512 doi:http://dx.doi.org/10.1074/jbc.M004485200
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