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Zusammenfassung:
Combinatorial reshuffling of subdomain-sized peptides may have pro-rotein Degradation targeting undruggables congressvided a very economic means for sequence space navigation and thusrotein Degradation targeting undruggables congressprotein fold evolution. Previously, through a bioinformatic study werotein Degradation targeting undruggables congressidentified a set of highly conserved, subdomain-sized motifs recurringrotein Degradation targeting undruggables congressacross distant folds, a cue that such motifs may have predated therotein Degradation targeting undruggables congressexisting pedigree of folds. This has led to the hypothesis that theserotein Degradation targeting undruggables congressancestral fragments may have provided the basic building blocks forrotein Degradation targeting undruggables congressmodern protein folds. We also demonstrated repetition of these frag-rotein Degradation targeting undruggables congressments as a mechanism in creating new folds. The aim of this workrotein Degradation targeting undruggables congresswas to investigate an alternative mechanism via recombination of het-rotein Degradation targeting undruggables congresserologous fragments, especially that we were unable to detect any suchrotein Degradation targeting undruggables congressrecombination incidents between the ancestral fragments in modernrotein Degradation targeting undruggables congressproteins. To provide an exemplar, we attempted to reconstruct arotein Degradation targeting undruggables congresspolymerase-beta N-terminal domain out of two conserved supersec-rotein Degradation targeting undruggables congressondary structures derived from two unrelated folds. We have done sorotein Degradation targeting undruggables congressusing a computational strategy that introduces a minimal number ofrotein Degradation targeting undruggables congressmutations to the constituting fragments. The resulting NMR structurerotein Degradation targeting undruggables congressagreed with the designed coordinates with atomic accuracy, demon-rotein Degradation targeting undruggables congressstrating that a recombination event and a few mutation are sufficientrotein Degradation targeting undruggables congressto evolve a new domain.
