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.
Original language | English (US) |
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Article number | 1852 |
Journal | Nature communications |
Volume | 12 |
Issue number | 1 |
DOIs | |
State | Published - Dec 1 2021 |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
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Structure of a new variant of GNCA ancestral beta-lactamase
Modi, T. (Contributor), Risso, V. A. (Contributor), Martinez-Rodriguez, S. (Contributor), Gavira, J. A. (Contributor), Mebrat, M. D. (Contributor), Van Horn, W. (Contributor), Sanchez-Ruiz, J. M. (Contributor) & Ozkan, B. (Contributor), Protein Data Bank (PDB), Mar 3 2021
DOI: 10.2210/pdb6YRS, https://www.wwpdb.org/pdb?id=pdb_00006yrs
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