Evolution of New Delhi metallo-beta-lactamase (NDM) in the clinic: iffects of NDM mutations on stability, zinc affinity, and mono-zinc activity. Secretion of GOB metallo-beta-lactamase in Escherichia coli depends strictly on the cooperation between the cytoplasmic DnaK chaperone system and the Sec machinery: completion of folding and Zn(II) ion acquisition occur in the bacterial periplasm. Transition metal sequestration by the host-defense protein calprotectin. Nutrient zinc at the host-pathogen interface. Clinical evolution of New Delhi metallo-beta-lactamase (NDM) optimizes resistance under Zn(II) deprivation. Membrane anchoring stabilizes and favors secretion of New Delhi metallo-beta-lactamase. Metallo-beta-lactamases in the age of multidrug resistance: from structure and mechanism to evolution, dissemination, and inhibitor design. Robustness–epistasis link shapes the fitness landscape of a randomly drifting protein. Quantitative description of a protein fitness landscape based on molecular features. Deciphering the evolution of metallo-β-lactamases: a journey from the test tube to the bacterial periplasm. Structural and mechanistic exploration of acid resistance: kinetic stability facilitates evolution of extremophilic behavior. Energetic landscape of α-lytic protease optimizes longevity through kinetic stability. Biological roles of protein kinetic stability. Quinary structure modulates protein stability in cells. Modulating protein stability-directed evolution strategies for improved protein function. Structural bases for stability-function tradeoffs in antibiotic resistance. Darwinian evolution can follow only very few mutational paths to fitter proteins. Missense meanderings in sequence space: a biophysical view of protein evolution. These observations link MBL-mediated resistance with the essential periplasmic metabolism, highlighting the importance of the cellular protein homeostasis.ĭePristo, M. ![]() NDM variants accumulate substitutions at the C terminus that quench its flexibility, enhancing their kinetic stability and bypassing proteolysis. ![]() ![]() Membrane anchoring makes apo-NDM-1 less accessible to Prc and protects it from DegP, a cellular protease degrading misfolded, nonmetalated NDM-1 precursors. Zn(II) binding renders the protein refractory to degradation by quenching the flexibility of this region. The nonmetalated (apo) NDM-1 is degraded by the periplasmic protease Prc that recognizes its partially unstructured C-terminal domain. Here we show that the metallo-β-lactamase (MBL) New Delhi MBL-1 (NDM-1) is a kinetically unstable protein on metal restriction that has evolved by acquiring different biochemical traits that optimize its in-cell stability. In contrast to the vast knowledge on protein stability in vitro, little is known about the factors governing in-cell stability. Protein stability is an essential property for biological function.
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