4XAY

Cycles of destabilization and repair underlie evolutionary transitions in enzymes

Summary for 4XAY

• Entry DOI: 10.2210/pdb4xay/pdb
• Related: 4PBE 4PBF 4PCN 4PCP 4XAF 4XAG 4XAZ 4XD3 4XD4 4XD5 4XD6
• Descriptor: Phosphotriesterase variant PTE-R8, ZINC ION, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (5 entities in total)
• Functional Keywords: dynamics, evolution, phosphotriesterase, hydrolase
• Biological source: Brevundimonas diminuta
• Total number of polymer chains: 2
• Total formula weight: 72615.21

Authors

Jackson, C.J.,Campbell, E.,Kaltenbach, M.,Tokuriki, N. (deposition date: 2014-12-16, release date: 2015-12-16, Last modification date: 2023-11-15)

Primary citation

Campbell, E.,Kaltenbach, M.,Correy, G.J.,Carr, P.D.,Porebski, B.T.,Livingstone, E.K.,Afriat-Jurnou, L.,Buckle, A.M.,Weik, M.,Hollfelder, F.,Tokuriki, N.,Jackson, C.J.
The role of protein dynamics in the evolution of new enzyme function.
Nat.Chem.Biol., 12:944-950, 2016

PubMed Abstract: Enzymes must be ordered to allow the stabilization of transition states by their active sites, yet dynamic enough to adopt alternative conformations suited to other steps in their catalytic cycles. The biophysical principles that determine how specific protein dynamics evolve and how remote mutations affect catalytic activity are poorly understood. Here we examine a 'molecular fossil record' that was recently obtained during the laboratory evolution of a phosphotriesterase from Pseudomonas diminuta to an arylesterase. Analysis of the structures and dynamics of nine protein variants along this trajectory, and three rationally designed variants, reveals cycles of structural destabilization and repair, evolutionary pressure to 'freeze out' unproductive motions and sampling of distinct conformations with specific catalytic properties in bi-functional intermediates. This work establishes that changes to the conformational landscapes of proteins are an essential aspect of molecular evolution and that change in function can be achieved through enrichment of preexisting conformational sub-states.

PubMed: 27618189
DOI: 10.1038/nchembio.2175

Experimental method

X-RAY DIFFRACTION (1.84 Å)