4E3T

Round 18 Arylesterase Variant of Phosphotriesterase with Bound Transition State Analog

Summary for 4E3T

• Entry DOI: 10.2210/pdb4e3t/pdb
• Descriptor: Phosphotriesterase, ZINC ION, hexyl(naphthalen-2-yloxy)phosphinic acid, ... (4 entities in total)
• Functional Keywords: phosphotriesterase, alpha/beta hydrolase, arylesterase, hydrolase
• Biological source: Brevundimonas diminuta
• Total number of polymer chains: 2
• Total formula weight: 73101.59

Authors

Tokuriki, N.,Jackson, C.J.,Tawfik, D.S. (deposition date: 2012-03-10, release date: 2013-01-23, Last modification date: 2023-11-08)

Primary citation

Tokuriki, N.,Jackson, C.J.,Afriat-Jurnou, L.,Wyganowski, K.T.,Tang, R.,Tawfik, D.S.
Diminishing returns and tradeoffs constrain the laboratory optimization of an enzyme
Nat Commun, 3:1257-1257, 2012

PubMed Abstract: Optimization processes, such as evolution, are constrained by diminishing returns-the closer the optimum, the smaller the benefit per mutation, and by tradeoffs-improvement of one property at the cost of others. However, the magnitude and molecular basis of these parameters, and their effect on evolutionary transitions, remain unknown. Here we pursue a complete functional transition of an enzyme with a >10(9)-fold change in the enzyme's selectivity using laboratory evolution. We observed strong diminishing returns, with the initial mutations conferring >25-fold higher improvements than later ones, and asymmetric tradeoffs whereby the gain/loss ratio of the new/old activity decreased 400-fold from the beginning of the trajectory to its end. We describe the molecular basis for these phenomena and suggest they have an important role in shaping natural proteins. These findings also suggest that the catalytic efficiency and specificity of many natural enzymes may be far from their optimum.

PubMed: 23212386
DOI: 10.1038/ncomms2246

Experimental method

X-RAY DIFFRACTION (1.65 Å)