Hinge-shift mechanism as a protein design principle for the evolution of β-lactamases from substrate promiscuity to specificity

Tushar Modi, Valeria A. Risso, Sergio Martinez-Rodriguez, Jose A. Gavira, Mubark D. Mebrat, Wade D. Horn, Jose M. Sanchez-Ruiz () and S. Banu Ozkan ()
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Tushar Modi: Arizona State University
Valeria A. Risso: Universidad de Granada
Sergio Martinez-Rodriguez: Universidad de Granada
Jose A. Gavira: Universidad de Granada
Mubark D. Mebrat: Arizona State University
Wade D. Horn: Arizona State University
Jose M. Sanchez-Ruiz: Universidad de Granada
S. Banu Ozkan: Arizona State University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract TEM-1 β-lactamase degrades β-lactam antibiotics with a strong preference for penicillins. Sequence reconstruction studies indicate that it evolved from ancestral enzymes that degraded a variety of β-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 β-lactamase, we engineer enzyme specificity that mimics the modern TEM-1 β-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.

Date: 2021
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DOI: 10.1038/s41467-021-22089-0

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