Conformational determinants for the recruitment of ercc1 by xpa in the nucleotide excision repair (ner) pathway: structure and dynamics of the xpa binding motif

Abstract

XPA is an essential protein in the nucleotide excision repair (NER) pathway, in charge of recruiting the ERCC1-XPF endonuclease complex to the DNA damage site. The only currently available structural insight into the binding of XPA to ERCC1 derives from the solution NMR structure of a complex between the ERCC1 central fragment and a 14-residue peptide, corresponding to the highly conserved binding motif of the XPA N-terminus, XPA(67-80). The extensive all-atom molecular-dynamics simulation study of the XPA(67-80) peptide both bound to the ERCC1 central fragment and free in solution presented here completes the profile of the structural determinants responsible for the ERCC1/XPA(67-80) complex stability. In addition to the wild-type, this study also looks at specific XPA(67-80) mutants in complex with the ERCC1 central domain and thus contributes to defining the conformational determinants for binding, as well as all of the essential structural elements necessary for the rational design of an XPA-based, ERCC1-specific inhibitor.