2afw: Difference between revisions

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-[[Image:2afw.gif|left|200px]]<br />
-<applet load="2afw" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="2afw, resolution 1.56&Aring;" />
-'''crystal structure of human glutaminyl cyclase in complex with N-acetylhistamine'''<br />
-==Overview==
+==Crystal structure of human glutaminyl cyclase in complex with N-acetylhistamine==
-N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or, glutamyl) precursor is required in the maturation of numerous bioactive, peptides. The aberrant formation of pGlu may be related to several, pathological processes, such as osteoporosis and amyloidotic diseases., This N-terminal cyclization reaction, once thought to proceed, spontaneously, is greatly facilitated by the enzyme glutaminyl cyclase, (QC). To probe this important but poorly understood modification, we, present here the structure of human QC in free form and bound to a, substrate and three imidazole-derived inhibitors. The structure reveals an, alpha/beta scaffold akin to that of two-zinc exopeptidases but with, several insertions and deletions, particularly in the active-site region., The relatively closed active site displays alternate conformations due to, the different indole orientations of Trp-207, resulting in two substrate, (glutamine t-butyl ester)-binding modes. The single zinc ion in the active, site is coordinated to three conserved residues and one water molecule, which is replaced by an imidazole nitrogen upon binding of the inhibitors., Together with structural and kinetic analyses of several, active-site-mutant enzymes, a catalysis mechanism of the formation of, protein N-terminal pGlu is proposed. Our results provide a structural, basis for the rational design of inhibitors against QC-associated, disorders.
+<StructureSection load='2afw' size='340' side='right'caption='[[2afw]], [[Resolution|resolution]] 1.56&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2afw]] 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=2AFW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AFW 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]] 1.56&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AHN:N-[2-(1H-IMIDAZOL-4-YL)ETHYL]ACETAMIDE'>AHN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=2afw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2afw OCA], [https://pdbe.org/2afw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2afw RCSB], [https://www.ebi.ac.uk/pdbsum/2afw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2afw ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/QPCT_HUMAN QPCT_HUMAN] Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-beta-amyloid. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides.<ref>PMID:15063747</ref> <ref>PMID:18486145</ref> <ref>PMID:21288892</ref>
+== 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/af/2afw_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=2afw ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-AFW 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 ZN, SO4 and AHN as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Glutaminyl-peptide_cyclotransferase Glutaminyl-peptide cyclotransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.5 2.3.2.5] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2AFW OCA].
+*[[Glutaminyl cyclase|Glutaminyl cyclase]]
+== References ==
-==Reference==
+<references/>
-Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation., Huang KF, Liu YL, Cheng WJ, Ko TP, Wang AH, Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13117-22. Epub 2005 Aug 31. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16135565 16135565]
+__TOC__
-[[Category: Glutaminyl-peptide cyclotransferase]]
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Cheng, W.J.]]
+[[Category: Cheng WJ]]
-[[Category: Huang, K.F.]]
+[[Category: Huang KF]]
-[[Category: Ko, T.P.]]
+[[Category: Ko TP]]
-[[Category: Liu, Y.L.]]
+[[Category: Liu YL]]
-[[Category: Wang, A.H.J.]]
+[[Category: Wang AHJ]]
-[[Category: AHN]]
-[[Category: SO4]]
-[[Category: ZN]]
-[[Category: alpha-beta protein]]
-[[Category: metalloprotein]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:50:39 2007''