2iu0: Difference between revisions

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-{{Seed}}
-[[Image:2iu0.png|left|200px]]
-<!--
+==crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase==
-The line below this paragraph, containing "STRUCTURE_2iu0", creates the "Structure Box" on the page.
+<StructureSection load='2iu0' size='340' side='right'caption='[[2iu0]], [[Resolution|resolution]] 2.53&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'>[[2iu0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=2b0w 2b0w]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IU0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IU0 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]] 2.53&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=203:1,5-DIHYDROIMIDAZO[4,5-C][1,2,6]THIADIAZIN-4(3H)-ONE+2,2-DIOXIDE'>203</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
-{{STRUCTURE_2iu0|  PDB=2iu0  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2iu0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2iu0 OCA], [https://pdbe.org/2iu0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2iu0 RCSB], [https://www.ebi.ac.uk/pdbsum/2iu0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2iu0 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/PUR9_CHICK PUR9_CHICK] Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.<ref>PMID:12501179</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/iu/2iu0_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=2iu0 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The inosine monophosphate cyclohydrolase (IMPCH) component (residues 1-199) of the bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase, residues 200-593)/IMPCH (ATIC) catalyzes the final step in the de novo purine biosynthesis pathway that produces IMP. As a potential target for antineoplastic intervention, we designed IMPCH inhibitors, 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (heterocycle, 1), the corresponding nucleoside (2), and the nucleoside monophosphate (nucleotide) (3), as mimics of the tetrahedral intermediate in the cyclization reaction. All compounds are competitive inhibitors against IMPCH (K(i) values = 0.13-0.23 microm) with the simple heterocycle 1 exhibiting the most potent inhibition (K(i) = 0.13 microm). Crystal structures of bifunctional ATIC in complex with nucleoside 2 and nucleotide 3 revealed IMPCH binding modes similar to that of the IMPCH feedback inhibitor, xanthosine 5'-monophosphate. Surprisingly, the simpler heterocycle 1 had a completely different IMPCH binding mode and was relocated to the phosphate binding pocket that was identified from previous xanthosine 5'-monophosphate structures. The aromatic imidazole ring interacts with a helix dipole, similar to the interaction with the phosphate moiety of 3. The crystal structures not only revealed the mechanism of inhibition of these compounds, but they now serve as a platform for future inhibitor improvements. Importantly, the nucleoside-complexed structure supports the notion that inhibitors lacking a negatively charged phosphate can still inhibit IMPCH activity with comparable potency to phosphate-containing inhibitors. Provocatively, the nucleotide inhibitor 3 also binds to the AICAR Tfase domain of ATIC, which now provides a lead compound for the design of inhibitors that simultaneously target both active sites of this bifunctional enzyme.
-===CRYSTAL STRUCTURES OF TRANSITION STATE ANALOGUE INHIBITORS OF INOSINE MONOPHOSPHATE CYCLOHYDROLASE===
+Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase.,Xu L, Chong Y, Hwang I, D'Onofrio A, Amore K, Beardsley GP, Li C, Olson AJ, Boger DL, Wilson IA J Biol Chem. 2007 Apr 27;282(17):13033-46. Epub 2007 Feb 26. PMID:17324932<ref>PMID:17324932</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2iu0" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_17324932}}, adds the Publication Abstract to the page
+*[[Bifunctional purine biosynthesis protein PURH|Bifunctional purine biosynthesis protein PURH]]
-(as it appears on PubMed at http://www.pubmed.gov), where 17324932 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_17324932}}
+__TOC__
+</StructureSection>
-==About this Structure==
-IU0 is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IU0 OCA].
-==Reference==
-<ref group="xtra">PMID:17324932</ref><ref group="xtra">PMID:15355974</ref><ref group="xtra">PMID:15615517</ref><ref group="xtra">PMID:11323713</ref><ref group="xtra">PMID:12501179</ref><ref group="xtra">PMID:12974624</ref><ref group="xtra">PMID:14756553</ref><ref group="xtra">PMID:14966129</ref><references group="xtra"/>
 [[Category: Gallus gallus]]
-[[Category: Amore, K.]]
+[[Category: Large Structures]]
-[[Category: Beardsley, G P.]]
+[[Category: Amore K]]
-[[Category: Boger, D L.]]
+[[Category: Beardsley GP]]
-[[Category: Chong, Y.]]
+[[Category: Boger DL]]
-[[Category: Hwang, I.]]
+[[Category: Chong Y]]
-[[Category: Li, C.]]
+[[Category: Hwang I]]
-[[Category: Olson, A J.]]
+[[Category: Li C]]
-[[Category: Onofrio, A D.]]
+[[Category: Olson AJ]]
-[[Category: Wilson, I A.]]
+[[Category: Onofrio AD]]
-[[Category: Xu, L.]]
+[[Category: Wilson IA]]
-[[Category: Atic]]
+[[Category: Xu L]]
-[[Category: Hydrolase]]
-[[Category: Impch]]
-[[Category: Inhibitor]]
-[[Category: Multifunctional enzyme]]
-[[Category: Purine biosynthesis]]
-[[Category: Structure-base]]
-[[Category: Transferase]]
-[[Category: Transition state analogue]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 22 10:57:18 2009''