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[[Image:1lrt.jpg|left|200px]]<br /><applet load="1lrt" size="350" color="white" frame="true" align="right" spinBox="true"
caption="1lrt, resolution 2.20&Aring;" />
'''CRYSTAL STRUCTURE OF TERNARY COMPLEX OF TRITRICHOMONAS FOETUS INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE: STRUCTURAL CHARACTERIZATION OF NAD+ SITE IN MICROBIAL ENZYME'''<br />


==Overview==
==CRYSTAL STRUCTURE OF TERNARY COMPLEX OF TRITRICHOMONAS FOETUS INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE: STRUCTURAL CHARACTERIZATION OF NAD+ SITE IN MICROBIAL ENZYME==
Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the conversion of IMP to XMP with the reduction of NAD(+), which is the rate-limiting step in the biosynthesis of guanine nucleotides. IMPDH is a promising target for chemotherapy. Microbial IMPDHs differ from mammalian enzymes in their lower affinity for inhibitors such as mycophenolic acid (MPA) and thiazole-4-carboxamide adenine dinucleotide (TAD). Part of this resistance is determined by the coupling between nicotinamide and adenosine subsites in the NAD(+) binding site that is postulated to involve an active site flap. To understand the structural basis of the drug selectivity, we solved the X-ray crystal structure of the catalytic core domain of Tritrichomonas foetus IMPDH in complex with IMP and beta-methylene-TAD at 2.2 A resolution. Unlike previous structures of this enzyme, the active site loop is ordered in this complex, and the catalytic Cys319 is 3.6 A from IMP, in the same plane as the hypoxanthine ring. The active site loop forms hydrogen bonds to the carboxamide of beta-Me-TAD which suggests that NAD(+) promotes the nucleophillic attack of Cys319 on IMP. The interactions of the adenosine end of TAD are very different from those in the human enzyme, suggesting the NAD(+) site may be an exploitable target for the design of antimicrobial drugs. In addition, a new K(+) site is observed at the subunit interface. This site is adjacent to beta-Me-TAD, consistent with the link between the K(+) activation and NAD(+). However, contrary to the coupling model, the flap does not cover the adenosine subsite and remains largely disordered.
<StructureSection load='1lrt' size='340' side='right'caption='[[1lrt]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1lrt]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Tritrichomonas_suis Tritrichomonas suis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LRT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1LRT 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]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=TAD:BETA-METHYLENE-THIAZOLE-4-CARBOXYAMIDE-ADENINE+DINUCLEOTIDE'>TAD</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=1lrt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1lrt OCA], [https://pdbe.org/1lrt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1lrt RCSB], [https://www.ebi.ac.uk/pdbsum/1lrt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1lrt ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/IMDH_TRIFO IMDH_TRIFO] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism.<ref>PMID:10029522</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/lr/1lrt_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=1lrt ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
1LRT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Tritrichomonas_foetus Tritrichomonas foetus] with <scene name='pdbligand=BOG:'>BOG</scene>, <scene name='pdbligand=K:'>K</scene>, <scene name='pdbligand=IMP:'>IMP</scene>, <scene name='pdbligand=TAD:'>TAD</scene> and <scene name='pdbligand=TRS:'>TRS</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/IMP_dehydrogenase IMP dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.205 1.1.1.205] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LRT OCA].
*[[Inosine monophosphate dehydrogenase 3D structures|Inosine monophosphate dehydrogenase 3D structures]]
 
== References ==
==Reference==
<references/>
Crystal structure of a ternary complex of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase: NAD+ orients the active site loop for catalysis., Gan L, Petsko GA, Hedstrom L, Biochemistry. 2002 Nov 5;41(44):13309-17. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12403633 12403633]
__TOC__
[[Category: IMP dehydrogenase]]
</StructureSection>
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Tritrichomonas foetus]]
[[Category: Tritrichomonas suis]]
[[Category: Gan, L.]]
[[Category: Gan L]]
[[Category: Hedstrom, L.]]
[[Category: Hedstrom L]]
[[Category: Petsko, G A.]]
[[Category: Petsko GA]]
[[Category: BOG]]
[[Category: IMP]]
[[Category: K]]
[[Category: TAD]]
[[Category: TRS]]
[[Category: alpha-beta barrel]]
[[Category: flap]]
[[Category: flexible loop]]
[[Category: ternary complex]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:47:47 2008''
Retrieved from "https://proteopedia.org/1lrt"