2018
DOI: 10.1038/s41467-018-03562-9
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Rescue of conformational dynamics in enzyme catalysis by directed evolution

Abstract: Rational design and directed evolution have proved to be successful approaches to increase catalytic efficiencies of both natural and artificial enzymes. Protein dynamics is recognized as important, but due to the inherent flexibility of biological macromolecules it is often difficult to distinguish which conformational changes are directly related to function. Here, we use directed evolution on an impaired mutant of the proline isomerase CypA and identify two second-shell mutations that partially restore its … Show more

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Cited by 124 publications
(111 citation statements)
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“…There are a number of examples from directed evolution studies where changes at second shell residues alter enzyme function (34, 46 -49). These substitutions can act by altering positions of active-site residues (46,48), reducing conformational heterogeneity (34), or altering enzyme dynamics (47,49). The N106S mutation acts by altering the hydrogen bond network of a loop structure that ultimately changes the position and conformational heterogeneity of active-site residues.…”
Section: ␤-Lactamase Variant Alters Enzyme Structure and Stabilitymentioning
confidence: 99%
“…There are a number of examples from directed evolution studies where changes at second shell residues alter enzyme function (34, 46 -49). These substitutions can act by altering positions of active-site residues (46,48), reducing conformational heterogeneity (34), or altering enzyme dynamics (47,49). The N106S mutation acts by altering the hydrogen bond network of a loop structure that ultimately changes the position and conformational heterogeneity of active-site residues.…”
Section: ␤-Lactamase Variant Alters Enzyme Structure and Stabilitymentioning
confidence: 99%
“…Protein dynamics is intimately linked to their function, regulation, degradation, and evolution [ 13 , 33 , 34 ]. Missense mutations may cause dramatic effects on protein function and regulation through modulation of protein dynamics [ 13 , 35 ], and the critical role of dynamics in enzyme evolution is becoming well established [ 36 , 37 , 38 ]. However, how disease-associated missense mutations cause loss of function linked to alterations in protein dynamics, and the modulation of their effects by interaction with compensatory mutations or PTMs have been rarely addressed.…”
Section: Control Of Protein Function and Life Cycle Through Structmentioning
confidence: 99%
“…In fact, most recent enzyme design protocols take into consideration multiple states to better represent the enzyme conformational heterogeneity. 18 …”
Section: Introductionmentioning
confidence: 99%