@misc{10481/68647,
year = {2021},
month = {3},
url = {http://hdl.handle.net/10481/68647},
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.},
organization = {United States Department of Health & Human Services

National Institutes of Health (NIH) - USA

R01GM112077},
organization = {Gordon and Betty Moore Foundations},
organization = {National Science Foundation (NSF)

1715591
1901709},
organization = {Spanish Ministry of Economy and Competitiveness/FEDER Funds 

BIO2015-66426-R
RTI2018-097142-B-100},
organization = {Human Frontier Science Program

RGP0041/2017},
organization = {FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento 

E.FQM.113.UGR18},
publisher = {Nature},
title = {Hinge-shift mechanism as a protein design principle for the evolution of β-lactamases from substrate promiscuity to specificity},
doi = {10.1038/s41467-021-22089-0},
author = {Modi, Tushar and Risso, Valeria Alejandra and Martínez Rodríguez, Sergio and Gavira Gallardo, José Antonio and Sánchez Ruiz, José Manuel},
}