View source for 3cem


==Human glycogen phosphorylase (tense state) in complex with the allosteric inhibitor AVE9423==
<StructureSection load='3cem' size='340' side='right'caption='[[3cem]], [[Resolution|resolution]] 2.47&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3cem]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3CEM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CEM FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AVD:1-(2-CARBOXYPHENYL)-7-CHLORO-6-[(2-CHLORO-4,6-DIFLUOROPHENYL)AMINO]-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC+ACID'>AVD</scene>, <scene name='pdbligand=NBG:1-N-ACETYL-BETA-D-GLUCOSAMINE'>NBG</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3ceh|3ceh]], [[3cej|3cej]]</div></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PYGL ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3cem FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cem OCA], [https://pdbe.org/3cem PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3cem RCSB], [https://www.ebi.ac.uk/pdbsum/3cem PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3cem ProSAT]</span></td></tr>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/PYGL_HUMAN PYGL_HUMAN]] Defects in PYGL are the cause of glycogen storage disease type 6 (GSD6) [MIM:[https://omim.org/entry/232700 232700]]. A metabolic disorder characterized by mild to moderate hypoglycemia, mild ketosis, growth retardation, and prominent hepatomegaly. Heart and skeletal muscle are not affected.<ref>PMID:9529348</ref>  
== Function ==
[[https://www.uniprot.org/uniprot/PYGL_HUMAN PYGL_HUMAN]] 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 ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ce/3cem_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3cem ConSurf].
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== Publication Abstract from PubMed ==
Glycogen phosphorylase (GP) is a validated target for the treatment of type 2 diabetes. Here we describe highly potent GP inhibitors, AVE5688, AVE2865, and AVE9423. The first two compounds are optimized members of the acyl urea series. The latter represents a novel quinolone class of GP inhibitors, which is introduced in this study. In the enzyme assay, both inhibitor types compete with the physiological activator AMP and act synergistically with glucose. Isothermal titration calorimetry (ITC) shows that the compounds strongly bind to nonphosphorylated, inactive GP (GPb). Binding to phosphorylated, active GP (GPa) is substantially weaker, and the thermodynamic profile reflects a coupled transition to the inactive (tense) conformation. Crystal structures confirm that the three inhibitors bind to the AMP site of tense state GP. These data provide the first direct evidence that acyl urea and quinolone compounds are allosteric inhibitors that selectively bind to and stabilize the inactive conformation of the enzyme. Furthermore, ITC reveals markedly different thermodynamic contributions to inhibitor potency that can be related to the binding modes observed in the cocrystal structures. For AVE5688, which occupies only the lower part of the bifurcated AMP site, binding to GPb (Kd = 170 nM) is exclusively enthalpic (Delta H = -9.0 kcal/mol, TDelta S = 0.3 kcal/mol). The inhibitors AVE2865 (Kd = 9 nM, Delta H = -6.8 kcal/mol, TDelta S = 4.2 kcal/mol) and AVE9423 (Kd = 24 nM, Delta H = -5.9 kcal/mol, TDelta S = 4.6 kcal/mol) fully exploit the volume of the binding pocket. Their pronounced binding entropy can be attributed to the extensive displacement of solvent molecules as well as to ionic interactions with the phosphate recognition site.

Thermodynamic characterization of allosteric glycogen phosphorylase inhibitors.,Anderka O, Loenze P, Klabunde T, Dreyer MK, Defossa E, Wendt KU, Schmoll D Biochemistry. 2008 Apr 22;47(16):4683-91. Epub 2008 Mar 29. PMID:18373353<ref>PMID:18373353</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Glycogen phosphorylase 3D structures|Glycogen phosphorylase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Phosphorylase]]
[[Category: Anderka, O]]
[[Category: Defossa, E]]
[[Category: Dreyer, M K]]
[[Category: Klabunde, T]]
[[Category: Loenze, P]]
[[Category: Schmoll, D]]
[[Category: Wendt, K U]]
[[Category: Allosteric enzyme]]
[[Category: Allosteric inhibitor]]
[[Category: Carbohydrate metabolism]]
[[Category: Disease mutation]]
[[Category: Glycogen metabolism]]
[[Category: Glycogen storage disease]]
[[Category: Glycosyltransferase]]
[[Category: Nucleotide-binding]]
[[Category: Phosphoprotein]]
[[Category: Protein ligand complex]]
[[Category: Pyridoxal phosphate]]
[[Category: Tense state]]
[[Category: Transferase]]