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1eh6

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[[Image:1eh6.jpg|left|200px]]<br /><applet load="1eh6" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1eh6, resolution 2.00&Aring;" />
 
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'''HUMAN O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE'''<br />
 
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==Overview==
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==HUMAN O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE==
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Human O(6)-alkylguanine-DNA alkyltransferase (AGT), which directly, reverses endogenous alkylation at the O(6)-position of guanine, confers, resistance to alkylation chemotherapies and is therefore an active, anticancer drug target. Crystal structures of active human AGT and its, biologically and therapeutically relevant methylated and benzylated, product complexes reveal an unexpected zinc-stabilized helical bridge, joining a two-domain alpha/beta structure. An asparagine hinge couples the, active site motif to a helix-turn-helix (HTH) motif implicated in DNA, binding. The reactive cysteine environment, its position within a groove, adjacent to the alkyl-binding cavity and mutational analyses characterize, DNA-damage recognition and inhibitor specificity, support a, structure-based dealkylation mechanism and suggest a molecular basis for, destabilization of the alkylated protein. These results support damaged, nucleotide flipping facilitated by an arginine finger within the HTH motif, to stabilize the extrahelical O(6)-alkylguanine without the protein, conformational change originally proposed from the empty Ada structure., Cysteine alkylation sterically shifts the HTH recognition helix to, evidently mechanistically couple release of repaired DNA to an opening of, the protein fold to promote the biological turnover of the alkylated, protein.
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<StructureSection load='1eh6' size='340' side='right'caption='[[1eh6]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1eh6]] is a 1 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=1EH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EH6 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=ZN:ZINC+ION'>ZN</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=1eh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1eh6 OCA], [https://pdbe.org/1eh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1eh6 RCSB], [https://www.ebi.ac.uk/pdbsum/1eh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1eh6 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/MGMT_HUMAN MGMT_HUMAN] Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) in DNA. Repairs alkylated guanine in DNA by stoichiometrically transferring the alkyl group at the O-6 position to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated.
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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/eh/1eh6_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=1eh6 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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1EH6 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=ZN:'>ZN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Methylated-DNA--[protein]-cysteine_S-methyltransferase Methylated-DNA--[protein]-cysteine S-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.63 2.1.1.63] Known structural/functional Site: <scene name='pdbsite=ACT:Active+Site+CYS'>ACT</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EH6 OCA].
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*[[DNA methyltransferase 3D structures|DNA methyltransferase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding., Daniels DS, Mol CD, Arvai AS, Kanugula S, Pegg AE, Tainer JA, EMBO J. 2000 Apr 3;19(7):1719-30. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10747039 10747039]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Methylated-DNA--[protein]-cysteine S-methyltransferase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Daniels DS]]
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[[Category: Daniels, D.S.]]
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[[Category: Tainer JA]]
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[[Category: Tainer, J.A.]]
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[[Category: ZN]]
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[[Category: alkyltransferase]]
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[[Category: dna repair]]
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[[Category: methyltransferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb 3 09:39:13 2008''
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Current revision

HUMAN O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE

PDB ID 1eh6

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