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Title: Structural Studies of MJ1529, an O6-methylguanine-DNAMethyltransferase

Abstract

The structure of an O{sub 6}-methylguanine methyltransferase from the thermophile Methanococcus jannaschii has been determined using multinuclear multidimensional NMR spectroscopy. The structure is similar to homologues from other organisms that have been determined by crystallography, with some variation in the N-terminal domain. The C-terminal domain is more highly conserved in both sequence and structure. Regions of the protein show broadening reflecting conformational flexibility that is likely related to function.

Authors:
; ;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director. Office of Science. Office of Biological andEnvironmental Research; National Science Foundation Grants DMB 8609035and BBS8720134
OSTI Identifier:
891630
Report Number(s):
LBNL-59310
Journal ID: ISSN 0749-1581; MRCHEG; R&D Project: GTL2KW; BnR: KP1102010; TRN: US200622%%272
DOE Contract Number:
DE-AC02-05CH11231
Resource Type:
Journal Article
Resource Relation:
Journal Name: Magnetic Resonance in Chemistry; Journal Volume: 44; Journal Issue: SI; Related Information: Journal Publication Date: 07/2006
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; CRYSTALLOGRAPHY; FLEXIBILITY; PROTEINS; SPECTROSCOPY; NMR protein structure DNA Methyltransferase DNA repair

Citation Formats

Roberts, Anne, Pelton, Jeffrey G., and Wemmer, David E. Structural Studies of MJ1529, an O6-methylguanine-DNAMethyltransferase. United States: N. p., 2006. Web.
Roberts, Anne, Pelton, Jeffrey G., & Wemmer, David E. Structural Studies of MJ1529, an O6-methylguanine-DNAMethyltransferase. United States.
Roberts, Anne, Pelton, Jeffrey G., and Wemmer, David E. Tue . "Structural Studies of MJ1529, an O6-methylguanine-DNAMethyltransferase". United States. doi:. https://www.osti.gov/servlets/purl/891630.
@article{osti_891630,
title = {Structural Studies of MJ1529, an O6-methylguanine-DNAMethyltransferase},
author = {Roberts, Anne and Pelton, Jeffrey G. and Wemmer, David E.},
abstractNote = {The structure of an O{sub 6}-methylguanine methyltransferase from the thermophile Methanococcus jannaschii has been determined using multinuclear multidimensional NMR spectroscopy. The structure is similar to homologues from other organisms that have been determined by crystallography, with some variation in the N-terminal domain. The C-terminal domain is more highly conserved in both sequence and structure. Regions of the protein show broadening reflecting conformational flexibility that is likely related to function.},
doi = {},
journal = {Magnetic Resonance in Chemistry},
number = SI,
volume = 44,
place = {United States},
year = {Tue Jan 10 00:00:00 EST 2006},
month = {Tue Jan 10 00:00:00 EST 2006}
}
  • In order to investigate the mechanisms of cellular damage by alkylating agents, human fibroblasts and tumor cell strains having different sensitivities to killing by N-methyl-N'-nitro-N-nitrosoguanidine (and different abilities to repair O6-methylguanine (O6mGua) in their DNA) were treated with other alkylating agents. Methyl methanesulfonate, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea, and N-ethyl-N'-nitro-N-nitrosoguanidine gave rise to sensitivity differences, but the differences were less than those observed with N-methyl-N'-nitro-N-nitrosoguanidine. After treatment with UV light, the strains showed similar survival. The data show that the DNA repair mechanism(s) responsible for the differential survival of the strains after N-methyl-N'-nitro-N-nitrosoguanidine treatment probably play(s) a role in repairing DNA damagemore » produced by methyl methanesulfonate, N-ethyl-N'-nitro-N-nitrosoguanidine, BCNU, and 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea but not that produced by UV. Furthermore, the results support the idea that a breakdown product of BCNU, that does not cause damage repairable by O6mGua repair mechanisms, contributes to the lethal effects due to BCNU-produced DNA-damage that is repairable by O6mGua repair mechanisms. The survival data, along with nucleoid sedimentation and adenovirus host-cell reactivation data, are consistent with the hypothesis that the lesion(s) lethal to tumor cells defective in O6mGua DNA repair are lesions in which DNA oxygen atoms are alkylated.« less
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