1xl1: Difference between revisions

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-[[Image:1xl1.gif|left|200px]]<br /><applet load="1xl1" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1xl1, resolution 2.10&Aring;" />
-'''Kinetic and crystallographic studies on 2-(beta-D-glucopyranosyl)-5-methyl-1,3,4-oxadiazole,-benzothiazole, and-benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site.'''<br />
-==Overview==
+==Kinetic and crystallographic studies on 2-(beta-D-glucopyranosyl)-5-methyl-1,3,4-oxadiazole,-benzothiazole, and-benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site.==
-In an attempt to identify leads that would enable the design of inhibitors, with enhanced affinity for glycogen phosphorylase (GP), that might control, hyperglycaemia in type 2 diabetes, three new analogs of, beta-D-glucopyranose, 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole were assessed for their, potency to inhibit GPb activity. The compounds showed competitive, inhibition (with respect to substrate Glc-1-P) with K(i) values of 145.2, (+/-11.6), 76 (+/-4.8), and 8.6 (+/-0.7) muM, respectively. In order to, establish the mechanism of this inhibition, crystallographic studies were, carried out and the structures of GPb in complex with the three analogs, were determined at high resolution (GPb-methyl-oxadiazole complex, 1.92 A;, GPb-benzothiazole, 2.10 A; GPb-benzimidazole, 1.93 A). The complex, structures revealed that the inhibitors can be accommodated in the, catalytic site of T-state GPb with very little change of the tertiary, structure, and provide a rationalization for understanding variations in, potency of the inhibitors. In addition, benzimidazole bound at the new, allosteric inhibitor or indole binding site, located at the subunit, interface, in the region of the central cavity, and also at a novel, binding site, located at the protein surface, far removed (approximately, 32 A) from the other binding sites, that is mostly dominated by the, nonpolar groups of Phe202, Tyr203, Val221, and Phe252.
+<StructureSection load='1xl1' size='340' side='right'caption='[[1xl1]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1xl1]] 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=1XL1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XL1 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>, <scene name='pdbligand=TH1:2-(BETA-D-GLUCOPYRANOSYL)-5-METHYL-BENZOTHIAZOLE'>TH1</scene></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=1xl1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xl1 OCA], [https://pdbe.org/1xl1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xl1 RCSB], [https://www.ebi.ac.uk/pdbsum/1xl1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xl1 ProSAT]</span></td></tr>
+</table>
+== 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.
+== 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/xl/1xl1_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=1xl1 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+In an attempt to identify leads that would enable the design of inhibitors with enhanced affinity for glycogen phosphorylase (GP), that might control hyperglycaemia in type 2 diabetes, three new analogs of beta-D-glucopyranose, 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole were assessed for their potency to inhibit GPb activity. The compounds showed competitive inhibition (with respect to substrate Glc-1-P) with K(i) values of 145.2 (+/-11.6), 76 (+/-4.8), and 8.6 (+/-0.7) muM, respectively. In order to establish the mechanism of this inhibition, crystallographic studies were carried out and the structures of GPb in complex with the three analogs were determined at high resolution (GPb-methyl-oxadiazole complex, 1.92 A; GPb-benzothiazole, 2.10 A; GPb-benzimidazole, 1.93 A). The complex structures revealed that the inhibitors can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provide a rationalization for understanding variations in potency of the inhibitors. In addition, benzimidazole bound at the new allosteric inhibitor or indole binding site, located at the subunit interface, in the region of the central cavity, and also at a novel binding site, located at the protein surface, far removed (approximately 32 A) from the other binding sites, that is mostly dominated by the nonpolar groups of Phe202, Tyr203, Val221, and Phe252.
-==About this Structure==
+Kinetic and crystallographic studies on 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site.,Chrysina ED, Kosmopoulou MN, Tiraidis C, Kardakaris R, Bischler N, Leonidas DD, Hadady Z, Somsak L, Docsa T, Gergely P, Oikonomakos NG Protein Sci. 2005 Apr;14(4):873-88. Epub 2005 Mar 1. PMID:15741340<ref>PMID:15741340</ref>
-XL1 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus] with TH1 and PLP 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=1XL1 OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-Kinetic and crystallographic studies on 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site., Chrysina ED, Kosmopoulou MN, Tiraidis C, Kardakaris R, Bischler N, Leonidas DD, Hadady Z, Somsak L, Docsa T, Gergely P, Oikonomakos NG, Protein Sci. 2005 Apr;14(4):873-88. Epub 2005 Mar 1. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15741340 15741340]
+</div>
+<div class="pdbe-citations 1xl1" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Glycogen phosphorylase 3D structures|Glycogen phosphorylase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
 [[Category: Oryctolagus cuniculus]]
-[[Category: Phosphorylase]]
+[[Category: Bischler N]]
-[[Category: Single protein]]
+[[Category: Chrysina ED]]
-[[Category: Bischler, N.]]
+[[Category: Docsa T]]
-[[Category: Chrysina, E.D.]]
+[[Category: Gergely P]]
-[[Category: Docsa, T.]]
+[[Category: Hadady Z]]
-[[Category: Gergely, P.]]
+[[Category: Kardakaris R]]
-[[Category: Hadady, Z.]]
+[[Category: Kosmopoulou MN]]
-[[Category: Kardakaris, R.]]
+[[Category: Leonidas DD]]
-[[Category: Kosmopoulou, M.N.]]
+[[Category: Oikonomakos NG]]
-[[Category: Leonidas, D.D.]]
+[[Category: Somsak L]]
-[[Category: Oikonomakos, N.G.]]
+[[Category: Tiraidis C]]
-[[Category: Somsak, L.]]
-[[Category: Tiraidis, C.]]
-[[Category: PLP]]
-[[Category: TH1]]
-[[Category: glycogenolysis]]
-[[Category: type 2 diabetes]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 06:08:20 2007''