Bjørås Magnar, Seeberg Erling, Luna Luisa, Pearl Laurence H, Barrett Tracey E
Department of Molecular Biology, Institute of Medical Microbiology, University of Oslo, The National Hospital, Norway.
J Mol Biol. 2002 Mar 22;317(2):171-7. doi: 10.1006/jmbi.2002.5400.
Both 8oxo-guanine and formamidopyrimidines are major products of oxidative DNA damage that can result in the fixation of transversion mutations following replication if left unrepaired. These lesions are targeted by the N-DNA glycosylase hOgg1, which catalyses excision of the aberrant base followed by cleavage of the phosphate backbone directly 5' to the resultant abasic site in a context, dependent manner. We present the crystal structure of native hOgg1 refined to 2.15 A resolution that reveals a number of highly significant conformational changes on association with DNA that are clearly required for substrate recognition and specificity. Changes of this magnitude appear to be unique to hOgg1 and have not been observed in any of the DNA-glycosylase structures analysed to date where both native and DNA-bound forms are available. It has been possible to identify a mechanism whereby the catalytic residue Lys 249 is "primed" for nucleophilic attack of the N-glycosidic bond.
8-氧代鸟嘌呤和甲酰胺嘧啶都是氧化性DNA损伤的主要产物，如果不进行修复，复制后可能导致颠换突变的固定。这些损伤由N-DNA糖基化酶hOgg1靶向，该酶催化异常碱基的切除，随后以依赖上下文的方式在所得无碱基位点的直接5'端切割磷酸主链。我们展示了天然hOgg1的晶体结构，其分辨率提高到2.15 Å，揭示了与DNA结合时许多高度显著的构象变化，这些变化显然是底物识别和特异性所必需的。这种程度的变化似乎是hOgg1独有的，在迄今为止分析的任何DNA糖基化酶结构中都未观察到，这些结构既有天然形式也有与DNA结合的形式。已经有可能确定一种机制，通过该机制催化残基赖氨酸249被“引发”以对N-糖苷键进行亲核攻击。
