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| | <StructureSection load='5llq' size='340' side='right'caption='[[5llq]], [[Resolution|resolution]] 2.70Å' scene=''> | | <StructureSection load='5llq' size='340' side='right'caption='[[5llq]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5llq]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Sacs2 Sacs2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LLQ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5LLQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5llq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharolobus_solfataricus_P2 Saccharolobus solfataricus P2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LLQ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.7Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ogt, SSO2487 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=273057 SACS2])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5llq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5llq OCA], [https://pdbe.org/5llq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5llq RCSB], [https://www.ebi.ac.uk/pdbsum/5llq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5llq ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5llq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5llq OCA], [http://pdbe.org/5llq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5llq RCSB], [http://www.ebi.ac.uk/pdbsum/5llq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5llq ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/OGT_SULSO OGT_SULSO]] 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/OGT_SACS2 OGT_SACS2] Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) and O4-methylthymine (O4-MeT) in DNA. Repairs the methylated nucleobase in DNA by stoichiometrically transferring the methyl group to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated.[HAMAP-Rule:MF_00772] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Sacs2]] | + | [[Category: Saccharolobus solfataricus P2]] |
| - | [[Category: Miggiano, R]] | + | [[Category: Miggiano R]] |
| - | [[Category: Rizzi, M]] | + | [[Category: Rizzi M]] |
| - | [[Category: Rossi, F]] | + | [[Category: Rossi F]] |
| - | [[Category: Dna dealkylation]]
| + | |
| - | [[Category: Inactive mutant]]
| + | |
| - | [[Category: Ogt]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
OGT_SACS2 Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) and O4-methylthymine (O4-MeT) in DNA. Repairs the methylated nucleobase in DNA by stoichiometrically transferring the methyl group to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated.[HAMAP-Rule:MF_00772]
Publication Abstract from PubMed
BACKGROUND: Alkylated DNA-protein alkyltransferases (AGTs) are conserved proteins that repair alkylation damage in DNA by using a single-step mechanism leading to irreversible alkylation of the catalytic cysteine in the active site. Trans-alkylation induces inactivation and destabilization of the protein, both in vitro and in vivo, likely triggering conformational changes. A complete picture of structural rearrangements occurring during the reaction cycle is missing, despite considerable interest raised by the peculiarity of AGT reaction, and the contribution of a functional AGT in limiting the efficacy of chemotherapy with alkylating drugs. METHODS: As a model for AGTs we have used a thermostable ortholog from the archaeon Sulfolobus solfataricus (SsOGT), performing biochemical, structural, molecular dynamics and in silico analysis of ligand-free, DNA-bound and mutated versions of the protein. RESULTS: Conformational changes occurring during lesion recognition and after the reaction, allowed us to identify a novel interaction network contributing to SsOGT stability, which is perturbed when a bulky adduct between the catalytic cysteine and the alkyl group is formed, a mandatory step toward the permanent protein alkylation. CONCLUSIONS: Our data highlighted conformational changes and perturbation of intramolecular interaction occurring during lesion recognition and catalysis, confirming our previous hypothesis that coordination between the N- and C-terminal domains of SsOGT is important for protein activity and stability. GENERAL SIGNIFICANCE: A general model of structural rearrangements occurring during the reaction cycle of AGTs is proposed. If confirmed, this model might be a starting point to design strategies to modulate AGT activity in therapeutic settings.
Interdomain interactions rearrangements control the reaction steps of a thermostable DNA alkyltransferase.,Morrone C, Miggiano R, Serpe M, Massarotti A, Valenti A, Del Monaco G, Rossi M, Rossi F, Rizzi M, Perugino G, Ciaramella M Biochim Biophys Acta. 2016 Oct 22;1861(2):86-96. doi:, 10.1016/j.bbagen.2016.10.020. PMID:27777086[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Morrone C, Miggiano R, Serpe M, Massarotti A, Valenti A, Del Monaco G, Rossi M, Rossi F, Rizzi M, Perugino G, Ciaramella M. Interdomain interactions rearrangements control the reaction steps of a thermostable DNA alkyltransferase. Biochim Biophys Acta. 2016 Oct 22;1861(2):86-96. doi:, 10.1016/j.bbagen.2016.10.020. PMID:27777086 doi:http://dx.doi.org/10.1016/j.bbagen.2016.10.020
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