6BM9

Directed evolutionary changes in MBL super family - VIM-2 Round 10

Summary for 6BM9

• Entry DOI: 10.2210/pdb6bm9/pdb
• Descriptor: Metallo-beta-lactamase, ZINC ION, GLYCEROL, ... (4 entities in total)
• Functional Keywords: phosphatase, directed evolution, mbl super family, ndm-1, hydrolase
• Biological source: Escherichia coli
• Total number of polymer chains: 4
• Total formula weight: 103973.34

Authors

Hong, N.-S.,Jackson, C.J.,Carr, P.D. (deposition date: 2017-11-13, release date: 2018-11-21, Last modification date: 2023-10-04)

Primary citation

Baier, F.,Hong, N.,Yang, G.,Pabis, A.,Miton, C.M.,Barrozo, A.,Carr, P.D.,Kamerlin, S.C.,Jackson, C.J.,Tokuriki, N.
Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes.
Elife, 8:-, 2019

PubMed Abstract: Genetic variation among orthologous proteins can cause cryptic phenotypic properties that only manifest in changing environments. Such variation may impact the evolvability of proteins, but the underlying molecular basis remains unclear. Here, we performed comparative directed evolution of four orthologous metallo-β-lactamases toward a new function and found that different starting genotypes evolved to distinct evolutionary outcomes. Despite a low initial fitness, one ortholog reached a significantly higher fitness plateau than its counterparts, via increasing catalytic activity. By contrast, the ortholog with the highest initial activity evolved to a less-optimal and phenotypically distinct outcome through changes in expression, oligomerization and activity. We show how cryptic molecular properties and conformational variation of active site residues in the initial genotypes cause epistasis, that could lead to distinct evolutionary outcomes. Our work highlights the importance of understanding the molecular details that connect genetic variation to protein function to improve the prediction of protein evolution.

PubMed: 30719972
DOI: 10.7554/eLife.40789

Experimental method

X-RAY DIFFRACTION (2.19 Å)