Peptides hit the catalysis walk

Article Biochemistry & Molecular Biology

Designer installation of a substrate recruitment domain to tailor enzyme specificity

Rodney Park et al.

Summary: Using computational interface design, a substrate recognition domain was installed on a promiscuous enzyme, allowing for directed modification of peptides. The designed enzyme SH3-588 methylates peptides with catalytic efficiencies exceeding the wild-type enzyme by over 1,000-fold. In competition experiments, the designer enzyme preferentially modifies directed substrates over undirected substrates, showing potential for specific post-translational modifications in complex multisubstrate environments.

NATURE CHEMICAL BIOLOGY (2023)

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Article Biochemistry & Molecular Biology

Perturbing the energy landscape for improved packing during computational protein design

Jack B. Maguire et al.

Summary: The FastDesign protocol in Rosetta is used to stabilize de novo designed protein structures and complexes by iterating between sequence optimization and structure refinement. By reducing repulsive forces to smoothen the energy landscape and promote sampling of alternative conformations and sequences, the protocol disfavors larger amino acids in the protein core. Through testing alternative ramping strategies for the repulsive weight, a scheme was developed that produces lower energy designs with more native-like sequence composition in the protein core, resulting in higher stability proteins.

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS (2021)

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Review Biochemical Research Methods

Engineering of new-to-nature ribosomally synthesized and post-translationally modified peptide natural products

Chunyu Wu et al.

Summary: Natural products have historically been important sources for drug development, particularly in combating infectious diseases. Recent advancements in genome mining have led to the discovery of highly unusual new reactions and the engineering of hybrid molecules with enhanced or completely new activities, which may pave the way for RiPPs to become potential next-generation therapeutics.

CURRENT OPINION IN BIOTECHNOLOGY (2021)

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Article Multidisciplinary Sciences

Conformational rearrangements enable iterative backbone N-methylation in RiPP biosynthesis

Fredarla S. Miller et al.

Summary: This study identified a novel type IV borosin 'split' pathway, which includes distinct α-N-methyltransferases and precursor peptide substrates, and revealed multiple conformational states. The findings provide rare insights into potential strategies for iterative maturation of RiPPs.

NATURE COMMUNICATIONS (2021)

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Article Chemistry, Multidisciplinary