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1pvn

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(New page: 200px<br /><applet load="1pvn" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pvn, resolution 2.00&Aring;" /> '''The crystal structur...)
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[[Image:1pvn.jpg|left|200px]]<br /><applet load="1pvn" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1pvn, resolution 2.00&Aring;" />
 
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'''The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP'''<br />
 
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==Overview==
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==The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP==
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Mizoribine monophosphate (MZP) is the active metabolite of the, immunosuppressive agent mizoribine and a potent inhibitor of IMP, dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP, with the concomitant reduction of NAD via a covalent intermediate at, Cys319 (E-XMP). Surprisingly, mutational analysis indicates that MZP is a, transition state analogue although its structure does not resemble that of, the expected transition state. Here we report the X-ray crystal structure, of the E.MZP complex at 2.0 A resolution that reveals a transition, state-like structure and solves the mechanistic puzzle of the IMPDH, reaction. The protein assumes a new conformation where a flap folds into, the NAD site and MZP, Cys319, and a water molecule are arranged in a, geometry resembling the transition state. The water appears to be, activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis, experiments confirm that this new closed conformation is required for the, hydrolysis of E-XMP, but not for the reduction of NAD. The closed, conformation provides a structural explanation for the differences in drug, selectivity and catalytic efficiency of IMPDH isozymes.
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<StructureSection load='1pvn' size='340' side='right'caption='[[1pvn]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1pvn]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Tritrichomonas_suis Tritrichomonas suis]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1mwf 1mwf]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PVN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PVN 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&#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=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MZP:4-CARBAMOYL-1-BETA-D-RIBOFURANOSYL-IMIDAZOLIUM-5-OLATE-5-PHOSPHATE'>MZP</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=1pvn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pvn OCA], [https://pdbe.org/1pvn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1pvn RCSB], [https://www.ebi.ac.uk/pdbsum/1pvn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1pvn 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/pv/1pvn_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=1pvn ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Mizoribine monophosphate (MZP) is the active metabolite of the immunosuppressive agent mizoribine and a potent inhibitor of IMP dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD via a covalent intermediate at Cys319 (E-XMP). Surprisingly, mutational analysis indicates that MZP is a transition state analogue although its structure does not resemble that of the expected transition state. Here we report the X-ray crystal structure of the E.MZP complex at 2.0 A resolution that reveals a transition state-like structure and solves the mechanistic puzzle of the IMPDH reaction. The protein assumes a new conformation where a flap folds into the NAD site and MZP, Cys319, and a water molecule are arranged in a geometry resembling the transition state. The water appears to be activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis experiments confirm that this new closed conformation is required for the hydrolysis of E-XMP, but not for the reduction of NAD. The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes.
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==About this Structure==
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The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase.,Gan L, Seyedsayamdost MR, Shuto S, Matsuda A, Petsko GA, Hedstrom L Biochemistry. 2003 Feb 4;42(4):857-63. PMID:12549902<ref>PMID:12549902</ref>
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1PVN 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 K, MZP and TRS as [http://en.wikipedia.org/wiki/ligands ligands]. This structure superseeds the now removed PDB entry 1MWF. 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=1PVN OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase., Gan L, Seyedsayamdost MR, Shuto S, Matsuda A, Petsko GA, Hedstrom L, Biochemistry. 2003 Feb 4;42(4):857-63. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12549902 12549902]
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</div>
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[[Category: IMP dehydrogenase]]
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<div class="pdbe-citations 1pvn" style="background-color:#fffaf0;"></div>
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[[Category: Single protein]]
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[[Category: Tritrichomonas foetus]]
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[[Category: Gan, L.]]
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[[Category: Hedstrom, L.]]
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[[Category: Matsuda, A.]]
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[[Category: Petsko, G.A.]]
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[[Category: Seyedsayamdost, M.]]
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[[Category: Shuto, S.]]
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[[Category: K]]
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[[Category: MZP]]
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[[Category: TRS]]
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[[Category: distal flap]]
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[[Category: drug selectivity]]
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[[Category: general base]]
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[[Category: imp dehydrogenase]]
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[[Category: mizoribine 5'-monophosphate]]
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[[Category: transition state analogue]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 00:09:39 2007''
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==See Also==
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*[[Inosine monophosphate dehydrogenase 3D structures|Inosine monophosphate dehydrogenase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Tritrichomonas suis]]
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[[Category: Gan L]]
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[[Category: Hedstrom L]]
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[[Category: Matsuda A]]
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[[Category: Petsko GA]]
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[[Category: Seyedsayamdost M]]
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[[Category: Shuto S]]

Current revision

The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP

PDB ID 1pvn

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