2ati: Difference between revisions

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-{{Seed}}
-[[Image:2ati.png|left|200px]]
-<!--
+==Glycogen Phosphorylase Inhibitors==
-The line below this paragraph, containing "STRUCTURE_2ati", creates the "Structure Box" on the page.
+<StructureSection load='2ati' size='340' side='right'caption='[[2ati]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[2ati]] 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=2ATI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ATI FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=IHU:N-(2-CHLORO-4-FLUOROBENZOYL)-N-(5-HYDROXY-2-METHOXYPHENYL)UREA'>IHU</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr>
-{{STRUCTURE_2ati|  PDB=2ati  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ati FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ati OCA], [https://pdbe.org/2ati PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ati RCSB], [https://www.ebi.ac.uk/pdbsum/2ati PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ati 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/at/2ati_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=2ati ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). The X-ray structure of screening hit 1 (IC50 = 2 microM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. A first cycle of chemical optimization supported by X-ray structural data yielded derivative 21, which inhibited hlGPa with an IC50 of 23 +/- 1 nM, but showed only moderate cellular activity in isolated rat hepatocytes (IC50 = 6.2 microM). Further optimization was guided by (i) a 3D pharmacophore model that was derived from a training set of 24 compounds and revealed the key chemical features for the biological activity and (ii) the 1.9 angstroms crystal structure of 21 in complex with hlGPa. A second set of compounds was synthesized and led to 42 with improved cellular activity (hlGPa IC50 = 53 +/- 1 nM; hepatocyte IC50 = 380 nM). Administration of 42 to anaesthetized Wistar rats caused a significant reduction of the glucagon-induced hyperglycemic peak. These findings are consistent with the inhibition of hepatic glycogenolysis and support the use of acyl ureas for the treatment of type 2 diabetes.
-===Glycogen Phosphorylase Inhibitors===
+Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes.,Klabunde T, Wendt KU, Kadereit D, Brachvogel V, Burger HJ, Herling AW, Oikonomakos NG, Kosmopoulou MN, Schmoll D, Sarubbi E, von Roedern E, Schonafinger K, Defossa E J Med Chem. 2005 Oct 6;48(20):6178-93. PMID:16190745<ref>PMID:16190745</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2ati" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_16190745}}, adds the Publication Abstract to the page
+*[[Glycogen phosphorylase 3D structures|Glycogen phosphorylase 3D structures]]
-(as it appears on PubMed at http://www.pubmed.gov), where 16190745 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_16190745}}
+__TOC__
+</StructureSection>
-==About this Structure==
-ATI is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ATI OCA].
-==Reference==
-Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes., Klabunde T, Wendt KU, Kadereit D, Brachvogel V, Burger HJ, Herling AW, Oikonomakos NG, Kosmopoulou MN, Schmoll D, Sarubbi E, von Roedern E, Schonafinger K, Defossa E, J Med Chem. 2005 Oct 6;48(20):6178-93. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16190745 16190745]
-Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs., Oikonomakos NG, Kosmopoulou MN, Chrysina ED, Leonidas DD, Kostas ID, Wendt KU, Klabunde T, Defossa E, Protein Sci. 2005 Jul;14(7):1760-71. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15987904 15987904]
-Activation of human liver glycogen phosphorylase by alteration of the secondary structure and packing of the catalytic core., Rath VL, Ammirati M, LeMotte PK, Fennell KF, Mansour MN, Danley DE, Hynes TR, Schulte GK, Wasilko DJ, Pandit J, Mol Cell. 2000 Jul;6(1):139-48. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10949035 10949035]
 [[Category: Homo sapiens]]
-[[Category: Phosphorylase]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: Brachvogel V]]
-[[Category: Brachvogel, V.]]
+[[Category: Burger HJ]]
-[[Category: Burger, H J.]]
+[[Category: Defossa E]]
-[[Category: Defossa, E.]]
+[[Category: Herling AW]]
-[[Category: Herling, A W.]]
+[[Category: Kadereit D]]
-[[Category: Kadereit, D.]]
+[[Category: Klabunde T]]
-[[Category: Klabunde, T.]]
+[[Category: Oikonomakos NG]]
-[[Category: Oikonomakos, N G.]]
+[[Category: Sarubbi E]]
-[[Category: Roedern, E von.]]
+[[Category: Schmoll D]]
-[[Category: Sarubbi, E.]]
+[[Category: Schoenafinger K]]
-[[Category: Schmoll, D.]]
+[[Category: Wendt KU]]
-[[Category: Schoenafinger, K.]]
+[[Category: Von Roedern E]]
-[[Category: Wendt, K U.]]
-[[Category: Glycogen phosphorylase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 07:20:29 2008''