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1b3o

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[[Image:1b3o.gif|left|200px]]<br /><applet load="1b3o" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1b3o, resolution 2.90&Aring;" />
 
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'''TERNARY COMPLEX OF HUMAN TYPE-II INOSINE MONOPHOSPHATE DEHYDROGENASE WITH 6-CL-IMP AND SELENAZOLE ADENINE DINUCLEOTIDE'''<br />
 
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==Overview==
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==TERNARY COMPLEX OF HUMAN TYPE-II INOSINE MONOPHOSPHATE DEHYDROGENASE WITH 6-CL-IMP AND SELENAZOLE ADENINE DINUCLEOTIDE==
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Inosine monophosphate dehydrogenase (IMPDH) controls a key metabolic step in the regulation of cell growth and differentiation. This step is the NAD-dependent oxidation of inosine 5' monophosphate (IMP) to xanthosine 5' monophosphate, the rate-limiting step in the synthesis of the guanine nucleotides. Two isoforms of IMPDH have been identified, one of which (type II) is significantly up- regulated in neoplastic and differentiating cells. As such, it has been identified as a major target in antitumor and immunosuppressive drug design. We present here the 2.9-A structure of a ternary complex of the human type II isoform of IMPDH. The complex contains the substrate analogue 6-chloropurine riboside 5'-monophosphate (6-Cl-IMP) and the NAD analogue selenazole-4-carboxamide adenine dinucleotide, the selenium derivative of the active metabolite of the antitumor drug tiazofurin. The enzyme forms a homotetramer, with the dinucleotide binding at the monomer-monomer interface. The 6 chloro-substituted purine base is dehalogenated, forming a covalent adduct at C6 with Cys-331. The dinucleotide selenazole base is stacked against the 6-Cl-IMP purine ring in an orientation consistent with the B-side stereochemistry of hydride transfer seen with NAD. The adenosine end of the ligand interacts with residues not conserved between the type I and type II isoforms, suggesting strategies for the design of isoform-specific agents.
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<StructureSection load='1b3o' size='340' side='right'caption='[[1b3o]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1b3o]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1B3O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1B3O 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]] 2.9&#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=CPR:6-CHLOROPURINE+RIBOSIDE,+5-MONOPHOSPHATE'>CPR</scene>, <scene name='pdbligand=SAE:SELENAZOLE-4-CARBOXYAMIDE-ADENINE+DINUCLEOTIDE'>SAE</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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=1b3o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1b3o OCA], [https://pdbe.org/1b3o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1b3o RCSB], [https://www.ebi.ac.uk/pdbsum/1b3o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1b3o ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/IMDH2_HUMAN IMDH2_HUMAN] 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. It may also have a role in the development of malignancy and the growth progression of some tumors.[HAMAP-Rule:MF_03156]
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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/b3/1b3o_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=1b3o 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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1B3O is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CPR:'>CPR</scene>, <scene name='pdbligand=SAE:'>SAE</scene> and <scene name='pdbligand=UNX:'>UNX</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=1B3O OCA].
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*[[Inosine monophosphate dehydrogenase|Inosine monophosphate dehydrogenase]]
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*[[Inosine monophosphate dehydrogenase 3D structures|Inosine monophosphate dehydrogenase 3D structures]]
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==Reference==
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__TOC__
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Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design., Colby TD, Vanderveen K, Strickler MD, Markham GD, Goldstein BM, Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3531-6. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10097070 10097070]
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: IMP dehydrogenase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Colby TD]]
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[[Category: Colby, T D.]]
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[[Category: Goldstein BM]]
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[[Category: Goldstein, B M.]]
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[[Category: Strickler MD]]
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[[Category: Strickler, M D.]]
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[[Category: Vanderveen K]]
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[[Category: Vanderveen, K.]]
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[[Category: CPR]]
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[[Category: SAE]]
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[[Category: UNX]]
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[[Category: dehydrogenase]]
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[[Category: guanine nucleotide synthesis]]
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[[Category: impd]]
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[[Category: impdh]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:51:06 2008''
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Current revision

TERNARY COMPLEX OF HUMAN TYPE-II INOSINE MONOPHOSPHATE DEHYDROGENASE WITH 6-CL-IMP AND SELENAZOLE ADENINE DINUCLEOTIDE

PDB ID 1b3o

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