Crystal structure of a thwarted mismatch glycosylase DNA repair complex.
The bacterial mismatch-specific uracil-DNA glycosylase (MUG) and eukaryotic thymine-DNA glycosylase (TDG) enzymes form a homologous family of DNA glycosylases that initiate base-excision repair of G:U/T mismatches. Despite low sequence homology, the MUG/TDG enzymes are structurally related to the ur...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
1999
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| _version_ | 1826292153099223040 |
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| author | Barrett, T Schärer, O Savva, R Brown, T Jiricny, J Verdine, G Pearl, L |
| author_facet | Barrett, T Schärer, O Savva, R Brown, T Jiricny, J Verdine, G Pearl, L |
| author_sort | Barrett, T |
| collection | OXFORD |
| description | The bacterial mismatch-specific uracil-DNA glycosylase (MUG) and eukaryotic thymine-DNA glycosylase (TDG) enzymes form a homologous family of DNA glycosylases that initiate base-excision repair of G:U/T mismatches. Despite low sequence homology, the MUG/TDG enzymes are structurally related to the uracil-DNA glycosylase enzymes, but have a very different mechanism for substrate recognition. We have now determined the crystal structure of the Escherichia coli MUG enzyme complexed with an oligonucleotide containing a non-hydrolysable deoxyuridine analogue mismatched with guanine, providing the first structure of an intact substrate-nucleotide productively bound to a hydrolytic DNA glycosylase. The structure of this complex explains the preference for G:U over G:T mispairs, and reveals an essentially non-specific pyrimidine-binding pocket that allows MUG/TDG enzymes to excise the alkylated base, 3, N(4)-ethenocytosine. Together with structures for the free enzyme and for an abasic-DNA product complex, the MUG-substrate analogue complex reveals the conformational changes accompanying the catalytic cycle of substrate binding, base excision and product release. |
| first_indexed | 2024-03-07T03:10:18Z |
| format | Journal article |
| id | oxford-uuid:b3f6f144-dbc1-4864-be81-2240809cab10 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:10:18Z |
| publishDate | 1999 |
| record_format | dspace |
| spelling | oxford-uuid:b3f6f144-dbc1-4864-be81-2240809cab102022-03-27T04:22:49ZCrystal structure of a thwarted mismatch glycosylase DNA repair complex.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b3f6f144-dbc1-4864-be81-2240809cab10EnglishSymplectic Elements at Oxford1999Barrett, TSchärer, OSavva, RBrown, TJiricny, JVerdine, GPearl, LThe bacterial mismatch-specific uracil-DNA glycosylase (MUG) and eukaryotic thymine-DNA glycosylase (TDG) enzymes form a homologous family of DNA glycosylases that initiate base-excision repair of G:U/T mismatches. Despite low sequence homology, the MUG/TDG enzymes are structurally related to the uracil-DNA glycosylase enzymes, but have a very different mechanism for substrate recognition. We have now determined the crystal structure of the Escherichia coli MUG enzyme complexed with an oligonucleotide containing a non-hydrolysable deoxyuridine analogue mismatched with guanine, providing the first structure of an intact substrate-nucleotide productively bound to a hydrolytic DNA glycosylase. The structure of this complex explains the preference for G:U over G:T mispairs, and reveals an essentially non-specific pyrimidine-binding pocket that allows MUG/TDG enzymes to excise the alkylated base, 3, N(4)-ethenocytosine. Together with structures for the free enzyme and for an abasic-DNA product complex, the MUG-substrate analogue complex reveals the conformational changes accompanying the catalytic cycle of substrate binding, base excision and product release. |
| spellingShingle | Barrett, T Schärer, O Savva, R Brown, T Jiricny, J Verdine, G Pearl, L Crystal structure of a thwarted mismatch glycosylase DNA repair complex. |
| title | Crystal structure of a thwarted mismatch glycosylase DNA repair complex. |
| title_full | Crystal structure of a thwarted mismatch glycosylase DNA repair complex. |
| title_fullStr | Crystal structure of a thwarted mismatch glycosylase DNA repair complex. |
| title_full_unstemmed | Crystal structure of a thwarted mismatch glycosylase DNA repair complex. |
| title_short | Crystal structure of a thwarted mismatch glycosylase DNA repair complex. |
| title_sort | crystal structure of a thwarted mismatch glycosylase dna repair complex |
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