This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DNA replication is a fundamental biological process required for cellular reproduction. The central feature of DNA replication is the template-induced nucleotidyl transfer reaction mediated by DNA polymerases. Critical to this function is the maintenance of high fidelity in the insertion of nucleotide in the event of polymerases-mediated elongation of the primer. It is widely accepted that the high fidelity of nucleotide insertion is controlled by closure of the DNA polymerases nucleotide-binding subdomain in response to binding the correct nucleotide. The model also holds that no such conformational change occurs in response to the incorrect nucleotides, yet no structural studies in support of the model exists for mismatched ternary complexes. Herein, we report the solution structural studies on monitoring different conformational states along the reaction pathway of high-fidelity of Pol beta (mammalian DNA polymerase beta) and of low-fidelity of Pol X (DNA polymerase X from African sworn fever virus). The reconstructed three-dimensional density maps on various forms of Pol beta and Pol X from one-dimensional small-angle X-ray solution data are found to be not only well-superimposed to the reported high-resolution crystal structures of Pol beta and Pol X, but also provide the novel information on many other complexes of Pol beta and Pol X with no structures available. Our current results suggest that a small but clear conformational change via the nucleotide-binding subdomain for the mismatched ternary complex of Pol beta.
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