6yrs

Publication Abstract from PubMed

TEM-1 beta-lactamase degrades beta-lactam antibiotics with a strong preference for penicillins. Sequence reconstruction studies indicate that it evolved from ancestral enzymes that degraded a variety of beta-lactam antibiotics with moderate efficiency. This generalist to specialist conversion involved more than 100 mutational changes, but conserved fold and catalytic residues, suggesting a role for dynamics in enzyme evolution. Here, we develop a conformational dynamics computational approach to rationally mold a protein flexibility profile on the basis of a hinge-shift mechanism. By deliberately weighting and altering the conformational dynamics of a putative Precambrian beta-lactamase, we engineer enzyme specificity that mimics the modern TEM-1 beta-lactamase with only 21 amino acid replacements. Our conformational dynamics design thus re-enacts the evolutionary process and provides a rational allosteric approach for manipulating function while conserving the enzyme active site.

Hinge-shift mechanism as a protein design principle for the evolution of beta-lactamases from substrate promiscuity to specificity.,Modi T, Risso VA, Martinez-Rodriguez S, Gavira JA, Mebrat MD, Van Horn WD, Sanchez-Ruiz JM, Banu Ozkan S Nat Commun. 2021 Mar 25;12(1):1852. doi: 10.1038/s41467-021-22089-0. PMID:33767175^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.