期刊
NUCLEIC ACIDS RESEARCH
卷 41, 期 3, 页码 1464-1482出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks1251
关键词
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资金
- Lawrence Livermore National Laboratory (DOE) [DE-AC52-07NA27344]
- UC-LLNS Fees grant
- University of California
- Lawrence Livermore National Security Fees Grant
RNA-dependent RNA polymerase (RdRp) is essential to viral replication and is therefore one of the primary targets of countermeasures against these dangerous infectious agents. Development of broad-spectrum therapeutics targeting polymerases has been hampered by the extreme sequence variability of these sequences. RdRps range in length from 400-800 residues, yet contain only similar to 20 residues that are conserved in most species. In this study, we made structure-based comparisons that are independent of sequence composition using a recently developed algorithm. We identified residue-to-residue correspondences of multiple protein structures and created (two-dimensional) structure-based alignment maps of 37 polymerase structures that provide both sequence and structure details. Using these maps, we determined that similar to 75% of each polymerase species consists of seven protein segments, each of which has high structural similarity to segments in other species, though they are widely divergent in sequence composition and order. We define each of these segments as a 'homomorph', and each includes (though most are much larger than) the well-known conserved polymerase motifs. All homomorphs contact the template tunnel or nucleoside triphosphate (NTP) entry tunnel and the exterior of the protein, suggesting they constitute a structural and functional skeleton common among the polymerases.
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