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Sequence reconstruction studies indicate that it evolved from ancestral enzymes that degraded a variety of \u03b2-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 \u03b2-lactamase, we engineer enzyme specificity that mimics the modern TEM-1 \u03b2-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.<\/jats:p>","DOI":"10.1038\/s41467-021-22089-0","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T07:04:17Z","timestamp":1616655857000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Hinge-shift mechanism as a protein design principle for the evolution of \u03b2-lactamases from substrate promiscuity to specificity"],"prefix":"10.1038","volume":"12","author":[{"given":"Tushar","family":"Modi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria A.","family":"Risso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6675-1550","authenticated-orcid":false,"given":"Sergio","family":"Martinez-Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7386-6484","authenticated-orcid":false,"given":"Jose A.","family":"Gavira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mubark D.","family":"Mebrat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2493-5578","authenticated-orcid":false,"given":"Wade D.","family":"Van Horn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9056-3928","authenticated-orcid":false,"given":"Jose M.","family":"Sanchez-Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9351-3758","authenticated-orcid":false,"given":"S.","family":"Banu Ozkan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"key":"22089_CR1","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/ismej.2008.86","volume":"3","author":"HK Allen","year":"2009","unstructured":"Allen, H. 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