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| | ==METHYLATED HUMAN O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE== | | ==METHYLATED HUMAN O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE== |
| - | <StructureSection load='1eh7' size='340' side='right' caption='[[1eh7]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='1eh7' size='340' side='right'caption='[[1eh7]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1eh7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EH7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1EH7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1eh7]] 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=1EH7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EH7 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SMC:S-METHYLCYSTEINE'>SMC</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SMC:S-METHYLCYSTEINE'>SMC</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1eh6|1eh6]], [[1eh8|1eh8]]</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=1eh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1eh7 OCA], [https://pdbe.org/1eh7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1eh7 RCSB], [https://www.ebi.ac.uk/pdbsum/1eh7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1eh7 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1eh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1eh7 OCA], [http://pdbe.org/1eh7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1eh7 RCSB], [http://www.ebi.ac.uk/pdbsum/1eh7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1eh7 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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. | + | [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. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | </div> | | </div> |
| | <div class="pdbe-citations 1eh7" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 1eh7" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[DNA methyltransferase 3D structures|DNA methyltransferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Daniels, D S]] | + | [[Category: Large Structures]] |
| - | [[Category: Tainer, J A]] | + | [[Category: Daniels DS]] |
| - | [[Category: Alkyltransferase]] | + | [[Category: Tainer JA]] |
| - | [[Category: Dna repair]]
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| - | [[Category: Methyltransferase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
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.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
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:10747039[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Daniels DS, Mol CD, Arvai AS, Kanugula S, Pegg AE, Tainer JA. Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding. EMBO J. 2000 Apr 3;19(7):1719-30. PMID:10747039 doi:10.1093/emboj/19.7.1719
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