1eh8: Difference between revisions

Revision as of 13:27, 21 February 2008

BENZYLATED HUMAN O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE

OverviewOverview

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.

About this StructureAbout this Structure

1EH8 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as [protein-cysteine_S-methyltransferase Methylated-DNA--[protein]-cysteine S-methyltransferase], with EC number 2.1.1.63 Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

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 [[Category: Methylated-DNA--[protein]-cysteine S-methyltransferase]]

Page seeded by OCA on Thu Feb 21 12:27:43 2008

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OCA

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 ==Overview==
-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.
+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.
 ==About this Structure==
@@ Line 14: / Line 14: @@
 [[Category: Methylated-DNA--[protein]-cysteine S-methyltransferase]]
 [[Category: Single protein]]
-[[Category: Daniels, D.S.]]
+[[Category: Daniels, D S.]]
-[[Category: Tainer, J.A.]]
+[[Category: Tainer, J A.]]
 [[Category: ZN]]
 [[Category: alkyltransferase]]
@@ Line 21: / Line 21: @@
 [[Category: methyltransferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 09:39:14 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:27:43 2008''