Negative Epistasis and Evolvability in TEM-1 β-Lactamase--The Thin Line between an Enzyme's Conformational Freedom and Disorder.

ABSTRACT: Epistasis is a key factor in evolution since it determines which combinations of mutations provide adaptive solutions and which mutational pathways toward these solutions are accessible by natural selection. There is growing evidence for the pervasiveness of sign epistasis--a complete reversion of mutational effects, particularly in protein evolution--yet its molecular basis remains poorly understood. We describe the structural basis of sign epistasis between G238S and R164S, two adaptive mutations in TEM-1 β-lactamase--an enzyme that endows antibiotics resistance. Separated by 10 Å, these mutations initiate two separate trajectories toward increased hydrolysis rates and resistance toward second and third-generation cephalosporins antibiotics. Both mutations allow the enzyme's active site

SUBMITTER: Dellus-Gur E 

PROVIDER: S-EPMC4718737 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature