View source for 1thz


==Crystal Structure of Avian AICAR Transformylase in Complex with a Novel Inhibitor Identified by Virtual Ligand Screening==
<StructureSection load='1thz' size='340' side='right'caption='[[1thz]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1thz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1THZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1THZ 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=326:2-{(E)-[5-HYDROXY-3-METHYL-1-(2-METHYL-4-SULFOPHENYL)-1H-PYRAZOL-4-YL]DIAZENYL}-4-SULFOBENZOIC+ACID'>326</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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=1thz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1thz OCA], [https://pdbe.org/1thz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1thz RCSB], [https://www.ebi.ac.uk/pdbsum/1thz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1thz 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/th/1thz_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=1thz ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase), one of the two folate-dependent enzymes in the de novo purine biosynthesis pathway, is a promising target for anti-neoplastic chemotherapy. Although classic antifolates, such as methotrexate, have been developed as anticancer agents, their general toxicity and drug resistance are major issues associated with their clinical use and future development. Identification of inhibitors with novel scaffolds could be an attractive alternative. We present here the crystal structure of avian AICAR Tfase complexed with the first non-folate based inhibitor identified through virtual ligand screening of the National Cancer Institute Diversity Set. The inhibitor 326203-A (2-[5-hydroxy-3-methyl-1-(2-methyl-4-sulfophenyl)-1H-pyrazol-4-ylazo]-4-su lfo-benzoic acid) displayed competitive inhibition against the natural cofactor, 10-formyl-tetrahydrofolate, with a K(i) of 7.1 mum. The crystal structure of AICAR Tfase with 326203-A at 1.8 A resolution revealed a unique binding mode compared with antifolate inhibitors. The inhibitor also accessed an additional binding pocket that is not occupied by antifolates. The sulfonate group of 326203-A appears to form the dominant interaction of the inhibitor with the proposed oxyanion hole through interaction with a helix dipole and Lys(267). An aromatic interaction with Phe(316) also likely contributes to favorable binding. Based on these structural insights, several inhibitors with improved potency were subsequently identified in the National Cancer Institute Compound Library and the Available Chemical Directory by similarity search and molecular modeling methods. These results provide further support for our combined virtual ligand screening rational design approach for the discovery of novel, non-folate-based inhibitors of AICAR Tfase.

Crystal structure of avian aminoimidazole-4-carboxamide ribonucleotide transformylase in complex with a novel non-folate inhibitor identified by virtual ligand screening.,Xu L, Li C, Olson AJ, Wilson IA J Biol Chem. 2004 Nov 26;279(48):50555-65. Epub 2004 Sep 7. PMID:15355974<ref>PMID:15355974</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 1thz" style="background-color:#fffaf0;"></div>

==See Also==
*[[Bifunctional purine biosynthesis protein PURH|Bifunctional purine biosynthesis protein PURH]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Gallus gallus]]
[[Category: Large Structures]]
[[Category: Li C]]
[[Category: Olson AJ]]
[[Category: Wilson IA]]
[[Category: Xu L]]