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1em6

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(New page: 200px<br /> <applet load="1em6" size="450" color="white" frame="true" align="right" spinBox="true" caption="1em6, resolution 2.20&Aring;" /> '''HUMAN LIVER GLYCOGE...)
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[[Image:1em6.gif|left|200px]]<br />
 
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<applet load="1em6" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1em6, resolution 2.20&Aring;" />
 
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'''HUMAN LIVER GLYCOGEN PHOSPHORYLASE A COMPLEXED WITH GLCNAC AND CP-526,423'''<br />
 
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==Overview==
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==HUMAN LIVER GLYCOGEN PHOSPHORYLASE A COMPLEXED WITH GLCNAC AND CP-526,423==
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Background: Glycogen phosphorylases catalyze the breakdown of glycogen to, glucose-1-phosphate for glycolysis. Maintaining control of blood glucose, levels is critical in minimizing the debilitating effects of diabetes, making liver glycogen phosphorylase a potential therapeutic, target.Results: The binding site in human liver glycogen phosphorylase, (HLGP) for a class of promising antidiabetic agents was identified, crystallographically. The site is novel and functions allosterically by, stabilizing the inactive conformation of HLGP. The initial view of the, complex revealed key structural information and inspired the design of a, new class of inhibitors which bind with nanomolar affinity and whose, crystal structure is also described. Conclusions: We have identified the, binding site of a new class of allosteric HLGP inhibitors. The crystal, structure revealed the details of inhibitor binding, led to the design of, a new class of compounds, and should accelerate efforts to develop, therapeutically relevant molecules for the treatment of diabetes.
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<StructureSection load='1em6' size='340' side='right'caption='[[1em6]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1em6]] 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=1EM6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EM6 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CP4:BIS[5-CHLORO-1H-INDOL-2-YL-CARBONYL-AMINOETHYL]-ETHYLENE+GLYCOL'>CP4</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NBG:1-N-ACETYL-BETA-D-GLUCOSAMINE'>NBG</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1em6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1em6 OCA], [https://pdbe.org/1em6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1em6 RCSB], [https://www.ebi.ac.uk/pdbsum/1em6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1em6 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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>
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== Function ==
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[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.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/em/1em6_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1em6 ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known disease associated with this structure: Glycogen storage disease VI OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=232700 232700]]
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*[[Glycogen phosphorylase 3D structures|Glycogen phosphorylase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1EM6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NBG, CP4, PLP and MPD 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EM6 OCA].
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__TOC__
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</StructureSection>
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==Reference==
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Human liver glycogen phosphorylase inhibitors bind at a new allosteric site., Rath VL, Ammirati M, Danley DE, Ekstrom JL, Gibbs EM, Hynes TR, Mathiowetz AM, McPherson RK, Olson TV, Treadway JL, Hoover DJ, Chem Biol. 2000 Sep;7(9):677-82. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10980448 10980448]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Phosphorylase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Ammirati M]]
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[[Category: Ammirati, M.]]
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[[Category: Danley DE]]
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[[Category: Danley, D.E.]]
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[[Category: Ekstrom JL]]
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[[Category: Ekstrom, J.L.]]
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[[Category: Hoover DJ]]
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[[Category: Hoover, D.J.]]
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[[Category: Hynes TR]]
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[[Category: Hynes, T.R.]]
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[[Category: Olson TV]]
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[[Category: Olson, T.V.]]
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[[Category: Rath VL]]
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[[Category: Rath, V.L.]]
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[[Category: CP4]]
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[[Category: MPD]]
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[[Category: NBG]]
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[[Category: PLP]]
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[[Category: allosteric binding]]
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[[Category: allosteric site]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:44:52 2007''
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Current revision

HUMAN LIVER GLYCOGEN PHOSPHORYLASE A COMPLEXED WITH GLCNAC AND CP-526,423

PDB ID 1em6

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