2hhu

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{{STRUCTURE_2hhu| PDB=2hhu | SCENE= }}
{{STRUCTURE_2hhu| PDB=2hhu | SCENE= }}
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'''C:O6-methyl-guanine in the polymerase postinsertion site (-1 basepair position)'''
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===C:O6-methyl-guanine in the polymerase postinsertion site (-1 basepair position)===
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==Overview==
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Methylating agents are widespread environmental carcinogens that generate a broad spectrum of DNA damage. Methylation at the guanine O(6) position confers the greatest mutagenic and carcinogenic potential. DNA polymerases insert cytosine and thymine with similar efficiency opposite O(6)-methyl-guanine (O6MeG). We combined pre-steady-state kinetic analysis and a series of nine x-ray crystal structures to contrast the reaction pathways of accurate and mutagenic replication of O6MeG in a high-fidelity DNA polymerase from Bacillus stearothermophilus. Polymerases achieve substrate specificity by selecting for nucleotides with shape and hydrogen-bonding patterns that complement a canonical DNA template. Our structures reveal that both thymine and cytosine O6MeG base pairs evade proofreading by mimicking the essential molecular features of canonical substrates. The steric mimicry depends on stabilization of a rare cytosine tautomer in C.O6MeG-polymerase complexes. An unusual electrostatic interaction between O-methyl protons and a thymine carbonyl oxygen helps stabilize T.O6MeG pairs bound to DNA polymerase. Because DNA methylators constitute an important class of chemotherapeutic agents, the molecular mechanisms of replication of these DNA lesions are important for our understanding of both the genesis and treatment of cancer.
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{{ABSTRACT_PUBMED_17179038}}
==About this Structure==
==About this Structure==
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[[Category: O6-methyl-guanine]]
[[Category: O6-methyl-guanine]]
[[Category: Protein-dna complex]]
[[Category: Protein-dna complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 06:18:49 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 17:34:58 2008''

Revision as of 14:35, 27 July 2008

Image:2hhu.png

Template:STRUCTURE 2hhu

C:O6-methyl-guanine in the polymerase postinsertion site (-1 basepair position)

Template:ABSTRACT PUBMED 17179038

About this Structure

2HHU is a Single protein structure of sequence from Geobacillus stearothermophilus. Full crystallographic information is available from OCA.

Reference

The structural basis for the mutagenicity of O(6)-methyl-guanine lesions., Warren JJ, Forsberg LJ, Beese LS, Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19701-6. Epub 2006 Dec 18. PMID:17179038

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