1lrt

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(New page: 200px<br /><applet load="1lrt" size="450" color="white" frame="true" align="right" spinBox="true" caption="1lrt, resolution 2.20&Aring;" /> '''CRYSTAL STRUCTURE OF...)
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[[Image:1lrt.jpg|left|200px]]<br /><applet load="1lrt" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1lrt, resolution 2.20&Aring;" />
 
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'''CRYSTAL STRUCTURE OF TERNARY COMPLEX OF TRITRICHOMONAS FOETUS INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE: STRUCTURAL CHARACTERIZATION OF NAD+ SITE IN MICROBIAL ENZYME'''<br />
 
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==Overview==
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==CRYSTAL STRUCTURE OF TERNARY COMPLEX OF TRITRICHOMONAS FOETUS INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE: STRUCTURAL CHARACTERIZATION OF NAD+ SITE IN MICROBIAL ENZYME==
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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.
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<StructureSection load='1lrt' size='340' side='right'caption='[[1lrt]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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== Structural highlights ==
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<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>
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</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>
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<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>
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<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>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/lr/1lrt_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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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 BOG, K, IMP, TAD and TRS 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1LRT OCA].
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*[[Inosine monophosphate dehydrogenase 3D structures|Inosine monophosphate dehydrogenase 3D structures]]
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== References ==
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==Reference==
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<references/>
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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]
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__TOC__
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[[Category: IMP dehydrogenase]]
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</StructureSection>
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Tritrichomonas foetus]]
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[[Category: Tritrichomonas suis]]
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[[Category: Gan, L.]]
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[[Category: Gan L]]
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[[Category: Hedstrom, L.]]
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[[Category: Hedstrom L]]
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[[Category: Petsko, G.A.]]
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[[Category: Petsko GA]]
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[[Category: BOG]]
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[[Category: IMP]]
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[[Category: K]]
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[[Category: TAD]]
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[[Category: TRS]]
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[[Category: alpha-beta barrel]]
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[[Category: flap]]
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[[Category: flexible loop]]
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[[Category: ternary complex]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 20:49:17 2007''
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Current revision

CRYSTAL STRUCTURE OF TERNARY COMPLEX OF TRITRICHOMONAS FOETUS INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE: STRUCTURAL CHARACTERIZATION OF NAD+ SITE IN MICROBIAL ENZYME

PDB ID 1lrt

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